research paper on repair

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• Published: 13 August 2018

Bonded repair of composite structures in aerospace application: a review on environmental issues

• S. Budhe   ORCID: orcid.org/0000-0002-3235-9232 1 ,
• M. D. Banea 1 &
• S. de Barros 1 , 2  

Applied Adhesion Science volume  6 , Article number:  3 ( 2018 ) Cite this article

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Over the last two decades, the repair of existing engineering structures using fiber reinforced polymer composites has attracted a great attention by aerospace industry, as it is more economical than replacing new. With an increased use of composite material in aerospace field, it is thus essential to restore the structural integrity by repair of damaged part. Concerns regarding the long term durability of composite repair bonded joints have been a major obstacle for critical component of aerospace structures. This paper reviews the current research on the environmental durability of adhesive bonded repair of composite structures to focus on the durability concerns and suggestion on the research needed in this area. The most important environmental factors (moisture and temperature) are reviewed thoroughly and also combined environmental effect. Finite element methods used to predict the environmental influence on the composite bonded joints are briefly reviewed. Finally, the paper concludes with key findings, opportunities and future research topics in order to develop cost effective, better quality and reliable composite repair bonded joints.

Introduction

Outstanding properties of fiber reinforced polymer composite materials, lead to a wide application in all the sectors such as aerospace, automotive, marine, sports industries and even in the civil infrastructures, etc. Since the last decades, an enormous use of composite materials in the aerospace sector has caused an increasing need for repair technology of damaged component rather than replacement with a new component [ 1 , 2 , 3 , 4 ]. Composite structures in service experience damage that comes from the accidental impact and mechanical or environmental condition [ 5 , 6 ]. The main environmental threats are related to the effect of temperature and moisture absorption, which can affect the strength of composite structures and reduce their service life [ 4 , 7 , 8 ]. The temperature and moisture levels could vary throughout the day (see Fig.  1 ), from take off to the landing or vice versa, during seasonal change or geographical difference [ 9 ]. This cyclic temperature and moisture could even further deteriorate the structures and then lead to premature failure of the structure.

Daily air temperature and relative humidity variation in Johor Bahru, Malaysia [ 9 ]

Composites are increasingly being used to repair both metallic and non-metallic (composite) structures. There are different types of composite repair bonded joints availables as shown in Fig.  2 . The most common types of repairs carried out with composite materials in the aerospace industry are external bonded patch repair and scarf repair. Both repair techniques differ from each other in terms of manufacturing and application point of view. The scarf repair joints require a special equipment to remove the considerable amount from parent material, so it is preferably used for thick laminate composite. On the other hand, external patch repair is relatively simple and faster, hence it is widely used in aircraft to keep an airplane in serviceable condition. Considerable experimental and numerical studies have been conducted to optimize the geometrical parameters of external patch repair and scarf repair joints for the better performance of the composite repair [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. However, designing an optimum scarf and patch repair of a composite structures is complex due to an unpredicted environmental condition during service period.

Type of composite repair bonded joints, a scarf repair, b stepped scarf repair, c scarf doubler bonded repair, d patch repair, e stepped lap repair

The application of adhesively bonded joints is widely used for the composite repair in aerospace structure because of the design flexibility, more fatigue resistant and higher damage tolerance than the other joining methods. Adhesive bonding method is already a well matured and developed process and was reviewed by many authors [ 18 , 19 , 20 , 21 , 22 ]. Many researchers [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ] studied the performance of adhesively bonded joints under the influence of different geometry and material parameters. Adhesive bonded repair in composite components are well established and developed in the aeronautical industry [ 31 , 32 , 33 ]. However, it is mainly restricted to the secondary structural component, due to the limit imposed by the fail-safe criteria.

Most of the composite repair systems in civil aircraft are implemented “in field” only and based on the cured-in-place (CIP) approach. This “in field” composite repair system introduces severe restrictions compared to those used in manufacturing plant such as: use of an autoclave, drying and curing methods, storing adhesive and composite laminate repair material, curing temperature etc. Bonded joints between the structure being repaired and the repair patch and the bonding agent (repair adhesive material) is the most critical part in terms of strength and durability of the repair. Many researchers conducted short term tests subjected to environmental condition by changing a number of variables such as the adhesive material, composite patch material, patch geometry, curing temperature etc. in order to determine the performance of repair bonded joints and optimize the joints [ 4 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. The main challenge is how to give an assurance of these repair joints for long term operation throughout their service life. This difficulty is caused by possible degradation of joint strength due to exposure to unpredicted environmental (predominantly) condition, specially moisture and temperature. To ensure that repair designs using bonded assemblies have an acceptable lifespan, the interaction of adhesive, composite and bonded joints with the service environments is required.

This review paper summarizes the research on the environmental issues mainly moisture and temperature on composite, adhesive and bonded joints, which help to set the moisture and temperature (design and selection of repair material) limit for the maximum performance of composite repair. Combined effect of moisture and temperature on the composite bonded joints is also discussed. Finally, in the conclusion section, several scientific challenges and prospects have been discussed in order to develop cost effective and high performance composite repair systems.

Background: bonded repair

Bonded composite repair of damaged structures have seen significant growth since the introduction of the composite repair system. The frequency of minor accidental damages during the operational life of the structure is high and their repair operations have a significant impact on the maintenance costs. Figure  3 summarizes the principal steps to follow for the repair of a damaged structure or component. If the material damage is not extensive, structural repair is the best solution as replacing the entire component is not cost-effective in many cases [ 42 , 43 ]. However, it is required to follow an exhaustive process to validate the repaired component, and if the component does not fulfil the structural requirements, then it is replaced by a new one.

Flow chart for the repair of a damaged structure made of composite

Figure  4 shows a chart which indicates the usual repair process and the time required to complete the activity. Usually a drying procedure is required before application of the repair patch to remove all the moisture in the skin absorbed during the service period of the aircraft [ 2 , 4 , 44 ]. The damage location is then cleaned and the repair laminates are placed. The repair patch/scarf is then cured on top of the original parent structure (aircraft part) using a heating blanket under vacuum, as unavailability of autoclave in “in field” composite repair system. It is clearly seen that the drying and curing process activity is taking more time compared to the other activities in the repair process. Drying time increases the repair costs dramatically, not only because of the energy wasted in the process, but also due to the lost revenue during this extended repair time and aircraft downtime [ 4 , 34 ]. Different trends in the mechanical performance of the composite bonded joins are observed with respect to the moisture content level and the adhesive material. Typical repair procedures recommend implementing a drying step before bonding. Currently, more attention is to reduce the drying time and curing temperature also, as both could reduce repair time and better performance of composite repair.

A summary of repair procedure of composite repair with time

Industry concerns

In recent years, the aerospace industry has acknowledged the need for standardized bonded repair process due to heavy use of composite material in aircraft, almost 40–50% of the volume in new aircrafts (i.e. Boeing 544) entering into service. Composite materials are widely used in both primary and secondary structural components, but industries are not well prepared to tackle the maintenance and repair of the secondary structural component of aircraft.

The current trends in aircraft operations are showing an increasing demand for lower operational and maintenance costs. However, durability concerns remain an obstacle to the application of composite repair in primary structure of aerospace components because of safe limit criterion. Many researchers [ 8 , 45 , 46 , 47 , 48 ] focused on durability and presented some trends, but it is difficult to generalize as it depends on a number of factors such as material properties, environmental conditions, manufacturing process and exposure time, etc. Hence proper selection of design parameters and process is a very important and requires a basic data base in order to obtain an optimum performance of the composite repair system. In order to meet these requirements, there are some obstacles such as availability of the autoclave system for curing, storage of repair adhesive material at particular condition and other facility for the composite bonded repair on site (field). Lack of complete long term data in the presence of environmental conditions, imposes a complete drying of components which ultimately lead to more repair time. In some instances, a compromise between the drying temperature and time for the curing of the damaged structure provided the best suitable combination. It is in the airliner’s best interest to produce a good quality repair in the most efficient way possible, namely by ensuring the implementation of a robust and low cost repair process.

Environmental parameters

The main environmental threats are related to the effect of temperature and moisture absorption, which can affect the strength of the composite structures and reduce their service life. In composite bonded joints, as in those used for repairs, the amount of moisture uptake by the composite structures depends on a number of factors such as: composite laminate, adhesive material, exposure conditions (temperature, humidity), exposure time, etc. [ 49 , 50 , 51 , 52 , 53 ]. The most important environmental parameters and their sources which are directly and indirectly associated with the durability of bonded joint performance are discussed below (Fig.  5 ).

Environmental factor and their sources which influencing the durability of adhesively composite bonded joints

• Temperature

The adhesives used in aerospace applications experience a wide range of temperature from cryogenic (− 55 °C) at high altitude to elevated temperature (200 °C), when travelling at mach 2 or above, during its service period. There has been a growing demand by industries, particularly in the aerospace industry for the adhesives to withstand high and low temperatures. Adhesive systems that can resist high temperature and high strength includes epoxies, silicones, phenolics, polyimides, bismaleimides and ceramics, etc. [ 19 ]. However, due to the polymeric nature of adhesives, the variation of the mechanical properties of the adhesives with temperature is generally the most important factor to consider when designing a bonded joint.

Figure  6 shows the tensile strength variation of adhesive with respect to the temperature for different adhesives [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]. The tensile strength values are normalized with respect to the value obtained at room temperature 22 °C for respective adhesives. It is clearly seen that the strength decreases at elevated temperature while at lower temperature, it increases with respect to the room temperature. At lower temperature adhesive get brittle in nature and at higher temperature the softening of adhesive takes place [ 54 , 56 , 57 , 58 , 62 ]. A similar trend was observed for all the adhesives, only the strength value differs and it depends on adhesive chemical properties. Retaining the maximum strength of the joints at both high and low temperatures is difficult as the adhesive behavior changes with respect to temperature. Therefore, the mechanical properties of the adhesive need to be measured from low to high temperature ranges, which can assure the performance of the composite repair for the specified temperature range.

Temperature dependent tensile strength properties of structural adhesives, test results from Refs. [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]

The strength of the adhesive is closely related to the glass transition temperature, T g , which is highly dependent on the cure temperature of the adhesive [ 57 , 59 , 63 , 64 , 65 ]. Curing at high temperature for short period improves the T g , which ultimately reduces the composite repair time. But, high initial curing temperature leads to a higher void formation, affecting the mechanical performance of the joint [ 50 , 63 , 66 ]. Cebrain et al. [ 67 ] proposed a dual step curing at isothermal stages (Fig.  7 ) which ensures a low void formation and thus maintaining a good mechanical performance. The overall processing time could be reduced from 4 h for the recommended cure cycle to 30 min with a cure cycle based on a dual step heating process, which accelerates the curing process. This dual step curing approach can reduce the void formation, which is essential in order to ensure the quality of adhesion, as a poorly cured adhesive is a critical issue for aeronautics industry.

Two step heating (curing) process [ 67 ]

Advanced adhesive can sustain the higher temperature in structural application but difficulties arise during composite repair where the high temperature properties need to be restored. Hence the curing temperature of the adhesive should be as low as possible around 177 °C, above which may risk as the auto-ignition temperature for the aviation fuel can be attempt [ 63 ]. Aerospace industries demand for lower curing temperature of adhesive as the repair takes place “in field” condition and composite repair systems need to cure at room temperature [ 35 , 36 ]. Table  1 presents the curing temperature of most used adhesives in aerospace and space application structures. The adhesives that can be stored at ambient temperature and cured at low temperature, with short cycle time, could be ideal for bonded repairs.

• Composite materials

An increasing use of fiber reinforced polymer (FRP) composites in large structural applications and development of polymer-matrix composite (PMC) materials with additional qualities requires a better understanding of the thermal and mechanical response at wide temperature range before application in aerospace and space structural.

In recent years, more experimental research was carried out into the effect of temperature on the mechanical properties of composite materials. Figure  8 shows the trend of tensile strength of GFRP specimens at different temperatures [ 74 ]. The results of these studies show a decrease in strength at higher temperatures while the strength increases at lower temperatures. The reduction is caused by the softening of the resin matrix when its T g is reached or near the test temperature [ 75 , 76 , 77 ]. This would weaken the interfaces between fibers and matrices and decrease the resistance of matrices during deformation [ 78 , 79 , 80 ]. But, thermal exposure up to temperatures below the T g is in fact advantageous for FRP composites and adhesives as a result of further post-curing [ 81 ]. Di Ludovico et al. [ 82 ] replaced the conventional resin matrix with an innovative epoxy with higher T g , in order to avoid failure at lower T g . On contrary, Takeda et al. [ 83 ] found that tensile strength increased with temperature for the thin graphite/epoxy cross-ply composite laminates, but decreased slightly for the thicker laminates at 80 °C. Patch thickness should be considered carefully during the design of bonded repair joints. Many researchers shows an improved strength of FRP composites at low temperature and a possible explanation for improved strength is FRP matrix embrittlement and matrix hardening [ 84 , 85 , 86 , 87 ]. The composite behavior at low temperatures depends to a large degree on the type of polymer matrix and its sub-zero mechanical properties.

Tensile strength of FRP composite coupon with respect to different temperature [ 74 ]

Fiber reinforced polymer composites are sensitive to temperature variations as a result of induced thermal stresses between the fibers and polymer matrix [ 88 ] which arises due to their distinct thermal expansion coefficients. Researchers [ 85 , 87 , 89 , 90 ] stated that the difference in contractions of fiber and matrix on cooling is also suspected to increase the residual stresses at the fiber/matrix interface, and then result in local micro-cracking and reduced tensile strength. Also at elevated temperatures, differential thermal expansion of fiber and matrix may lead to the formation of microcracks at the fiber/polymer interface [ 91 , 92 ]. The magnitude of the residual stresses is proportional to the difference in curing and operating temperatures of the composite material [ 93 ]. The effect of a thermal environment on the residual mechanical performance was evaluated and found both the flexural and shear strength decreased and became more pronounced at prolonged exposure time due to weakening of the interface [ 94 ]. In order to utilize the full capability of the advanced and new composites, its behavior under high and low temperature conditions and stress must be studied in detail.

Adhesive joints

The influence of temperature on the strength of adhesive joints is an important factor to consider in the design of adhesive joints. The strength of adhesive joints at different temperature depends on the coefficients of thermal expansion (CTE), cure shrinkage of adhesive and properties of the adhesive and adherend. Many researchers [ 95 , 96 , 97 , 98 , 99 , 100 ] studied the temperature effect on the composite bonded joint strength. Generally adhesive joints strength degrades at higher temperature and improves at lower temperatures. The quasi-static tensile behavior of adhesively-bonded double-lap joints, composed of pultruded GFRP laminates and an epoxy adhesive, was investigated under temperatures ranging between − 35 °C and 60 °C. The highest strength was obtained at 40 °C due to a statistical size effect caused by the smoothing of the normal tensile and shear stress peaks [ 97 ]. At temperatures above T g , strength and stiffness decreased following the trend of the thermomechanical behavior of the adhesive [ 97 , 98 ]. It would be beneficial to select the adhesive and composite patch material with higher glass transition temperature, which allow a better performance of the repair joint at higher temperature too.

Temperature variations (thermal cycle) are among the most important environmental factors that may affect the durability of adhesively bonded joints for aerospace applications. Sousa et al. [ 95 ] studied the effects of thermal cycles on adhesively bonded joints between pultruded glass fibre reinforced polymer. The maximum performance reduction of Elastic Polymer-GFRP joints occurred after 150 thermal cycles, when the ultimate load and stiffness decreased by 18% and 22%, respectively. Little changes occurred with additional thermal cycles, which were partly attributed to the occurrence of post-cure phenomena in the elastic polymer adhesive during exposure at higher temperatures [ 95 ]. A small number thermal cycles would be advantageous to the joint as an occurrence of post-cure. Residual thermal stresses are induced at higher temperature of the joint due to the CTE mismatch between the adhesive and the adherends [ 101 ]. The higher temperatures facilitate polymer chain mobility and lead to some degree of relaxation of these stresses. However, when cooling the joint, the stress relaxation is reflected in an increased interfacial stress between the substrate and adhesive layer.

Fracture toughness of the composite laminate bonded joints is widely used to predict the performance of composite bonded joints under different temperature condition. It has generally been found that there is an increase in fracture toughness, G IC , with increasing temperature while at lower temperature decreases with respect to the room temperature under mode I tensile loading (DCB specimens) as shown in Fig.  9 [ 7 , 102 , 103 , 104 , 105 , 106 , 107 ]. The fracture toughness values are normalized with respect to the value obtained at room temperature 22 °C. An increase of the matrix ductility, an increment in the amount of fiber bridging and fiber breakage are the most common explanation for the improvement in fracture toughness [ 103 , 105 , 107 , 108 , 109 , 110 ]. On the other hand, if test temperature is above the T g , the fracture toughness decreases due to the loss of adhesion between the fibers and the matrix (Rubbery state), but below the T g , it was observed an increase in G IC due to strongest bond strength between the fiber and the matrix [ 108 ]. While, Russell et al. [ 111 ] suggested that the decrease was likely related to both residual stress states in the matrix around the fiber and to the fibers constraining the size of the adhesive. In pure mode II tests, however, do not exhibit the same trend, some of the authors observed a decrease G Ic , while some found increased values with respect to the test temperature [ 5 , 103 , 106 , 111 ]. A small number of results for the mixed mode I–II behaviour have been published, but still there is not a clear consensus about the trend of fracture toughness value with the effect of temperature under mixed loading [ 7 , 111 , 112 ].

Fracture toughness with respect to the temperature [ 7 , 102 , 103 , 104 , 105 , 106 , 107 ]

It was shown in the literature that there are many mechanisms such as: matrix deformation (G m ), fibre bridging (G b ), fibre fracture (G f ), and fibre/matrix interfacial debonding (G deb ) that contribute to increase or decrease of the fracture toughness, but still not confirmed about quantities of each mechanism. Activation of each mechanism depends on different parameters such as adhesive- adherend material properties, test temperature, curing temperature, glass transition temperature, moisture content, etc. Mixed trend of fracture toughness was observed over the temperature range under different loading condition. Hence, it is important to consider the glass transition temperature and the expected maximum temperature that can be reached by the composite structure during service period, while selection of adhesive and composite patch for repair.

Moisture primarily affects the resins and adhesives in FRP composites and bonded assemblies structures. Generally, the adhesive absorbs more moisture content than the composite laminate, matrix and interface in any composite structure. Each adhesive type absorbs moisture up to certain extent and its absorption rate and saturation limits are dependent on a number of factors such as exposure condition, exposure time, temperature and humidity level, etc. So, the moisture absorption data of each adhesive in different environmental condition for long duration are almost difficult to have. Instead of it, the worst possible, attack by the moisture on the adhesive is considered for the design purpose to maintain the safe design.

In general moisture can change adhesive properties through plasticization, swelling, cracking and hydrolysis phenomenon. Figure  10 shows the representative moisture curve of sorption, desorption and resorption level of particular adhesive [ 113 ]. Faster resorption and higher saturation limit in a subsequent cycle compared to previous one indicate a change in physical and chemical properties after a cycle of sorption and desorption. It has been reported that the penetration of the moisture into the polymer will increase the free volume by the swelling effect and cracking during moisture absorption [ 114 , 115 ]. A subsequent step, in resorption cycles, this free volume occupies the moisture in the resorption process which adds more moisture content and faster than the previous cycle. Desorption from highly moisture saturation tended to leave small residual moisture content, which could only be removed by heating at high enough temperature but blistering may occur [ 116 , 117 ]. So, for composite repair structure the knowledge of desorption, resorption and a saturation limit should be needed as the structure face higher impact than previous as proved by earlier studies.

Moisture curve of sorption, desorption and resorption level of adhesive [ 113 ]

The effects of the moisture on the mechanical behavior of the epoxy system have been studied by many researchers [ 113 , 118 , 119 , 120 , 121 ]. The detailed trend of tensile strength and elastic modulus is shown in Fig.  11 [ 50 , 73 , 113 , 118 , 119 , 120 , 121 , 122 ]. The possible reasons for the degradation of the strength are plasticization, decreasing the values of the glass transition temperature, stress generation due to the swelling of the system and a possible chemical degradation [ 113 , 114 , 118 , 123 , 124 ]. The lower percentage of moisture in the adhesive won’t be a major issue as long as post-cure will absorb during curing process, but void content may introduced. It was noted that the glass transition temperature, T g value decreased with moisture (plasticise the epoxy) and softening of the adhesive [ 73 , 121 , 125 , 126 , 127 , 128 ]. Therefore, it is important to have the moisture absorption history of the adhesive, which is going to use for repair and its mechanical behaviour and also consider moisture accumulation by the adhesive during the storage in freezer.

Normalised tensile strength at various levels of moisture uptake [ 50 , 73 , 113 , 118 , 119 , 120 , 121 , 122 ]

The moisture uptake by the composites is consist of polymer matrix, interface of matrix-fiber and very negligible by the fiber. Moisture absorption by the composite is mainly conducted by the diffusion mechanism. The other two mechanisms of moisture penetration into composite materials are capillary flow along the fiber/matrix interface and finally, percolating flow and storage of water in micro-cracks. These two damage-dependent mechanisms are increasing both the rate and the maximum capacity of moisture absorption in an auto-accelerative manner [ 51 , 129 , 130 , 131 ]. The degree of absorption depends on both matrix and fiber properties, matrix-fiber interface, fiber volume fraction, composite void content and epoxy resin curing agent ratio, etc. [ 132 , 133 , 134 ]. Moisture absorption by composite laminate during repair time is not only the concern but also the moisture that might be absorbed by uncured composites (prepreg) during storage. Finally, repair materials that are left uncovered during the multi-step process of bonded repairs may also absorb and trap atmospheric moisture.

Figure  12 shows the moisture uptake during the first four absorption cycles. The moisture level and diffusivity of composites increases during each subsequent reabsorption cycles [ 51 ]. This behavior has been associated with the penetrant molecules can rearrange the polymer network, causing swelling of the material and micro-cracking occurring in the matrix during each sorption. As already mentioned, moisture absorption may induce irreversible changes to polymers and composites, such as chemical degradation, cracking and debonding [ 131 , 134 , 135 , 136 ]. Hence, topics such as the reversibility of the wet/dry cycle, the damage induced by the absorption process and the effect of this damage on the later stages of the absorption process and on subsequent cycles, are of practical interest and important for the composite repair applications. This data would help for proper selection of composite patch material in the composite repair.

Moisture sorption by Gr/Ep composite laminate in subsequent steps [ 51 ]

The influence of moisture absorption on mechanical properties of FRP composites is well documented in literature, regarding the tensile, interlaminar shear and flexural properties [ 122 , 132 , 137 , 138 , 139 , 140 , 141 , 142 ]. The absorbed moisture results in more detrimental effects on the mechanical properties of composite materials since the water not only interacts with polymer matrices, physically, i.e. plasticization, but it also attacks the fiber–matrix interface [ 143 , 144 , 145 ]. A reduction in strength and stiffness due to moisture absorption can be attributed to various damage mechanisms which can include matrix cracking, fibre/matrix interface, matrix plasticization/softening, stress generation due to swelling of the system, chemical degradation [ 122 , 138 , 139 , 146 , 147 ].

Akay et al. [ 8 ] reported that water uptake is also further detrimental to fibre–matrix adhesion strength. This has been supported by an increase of bare fibres on SEM inspections of fractured surfaces, which indicate a weak adhesion between matrix and fiber. Also strong mismatch in swelling behaviour between the matrix and the fibre was observed, which may introduce weak adhesion integrity [ 148 ]. The drying of FRP composites is compulsory but complete drying also lead to damage the FRP composite by introducing the micro-cracking during desorption, so it is important to consider the drying temperature and time, in order to avoid any damage caused by drying [ 149 ]. Presence of moisture in composites may affect the properties of the repair as it can cause an increase in bond line porosity and a decrease in joint strength.

The majority of the research papers recommend drying the composite substrates before bonding to prevent the diffusion of moisture from the substrate into the joint during repair cure cycle. For increased durability of composite materials, their capacity for sustained performance under harsh and changing environmental conditions must be quantified.

Long term durability of joints in severe environments has been recognized as one of the obstacles to the widespread application of adhesive, specially for aerospace, marine, and offshore structure which exposed to severe environmental conditions. Composite structure absorbs more moisture through the atmospheric condition during its service period, but we could not neglect the moisture absorbed by an individual components such as composite laminate, adhesive before bonding process. The moisture absorbs before bonding called pre-bond moisture and after the bonding term as post-bond moisture. In subsequent sections, both pre-bond and post-bond moisture are described individually in details.

Pre-bond moisture

Pre-bond moisture issue is very important for joints formed between polymeric-composite substrates as it directly influences on the performance of adhesive joints. There are several potential sources of pre-bond moisture in composite substrates such as: during the manufacturing process, CFRP panel undergoes several treatment procedures like wet abrasion, water break test, transportation of CFRP panel from one place to another, storing the laminate for longer periods in freezer and exposing to environmental conditions during composite repair in field etc. [ 44 , 47 , 150 , 151 ].

There are limited studies [ 4 , 34 , 41 , 44 , 47 ] reported on the pre-bond moisture effect on the mechanical properties of the bonded joints and most of them found the decrease in strength when the moisture is present in the composite. Parker et al. [ 41 ] studied the effect of composite pre-bond moisture and found a reduction in single lap-shear joint strength. Voiding, plasticization of the adhesive, and a reduction in interfacial adhesion are the possible causes for the reduction in strength [ 41 , 152 , 153 ].

An increase in the pre-bond moisture of the composite substrate yielded an increase in void content of the joint further support for higher degradation [ 41 ]. Drying the composite substrates and curing the bonded joints under isostatic pressure was found to prevent the occurrence of voids [ 44 , 47 , 154 ]. Most of the entrapped air could be evacuated prior to cure for the method using a textured adhesive film. These air evacuation strategies reduced the bondline void and exhibited a higher strength of repair bonded joints [ 39 , 63 ]. Previous work on BMI adhesives suggested that void reduction was also possible if vacuum was removed at the adhesive flow temperature and small positive pressure was maintained during cure [ 155 ].

A small amount of pre-bond moisture (below 0.5% w/w) appears to have a positive or no/little effect on the strength of the repaired joint, but as the moisture level increases, the repair strength falls [ 4 ]. However, pre-bond moisture of about 1.3% would cause a 20% loss in the tensile strength of the joint, whereas the flexural strength of the joints was not affected. For example, the flexural strength of repairs of XAS/913 parent panels with XAS/913 (using BSL 312/5 adhesive) appeared to be only weakly dependent on the pre-bond moisture level up to 1.3%. There was a slight decline in strength with moisture content up to a moisture content of around 1.2% or 1.3%, after which the decrease becomes far more rapid. It is clear that if the composite content small percentage of moisture (0.5% w/w) then complete drying before repair is not always necessary. Generally, the moisture levels usually found in composite components in service are typically 0.8% w/w. Research is needed to establish whether the effect of pre-bond moisture is always detrimental or whether a small percentage of moisture in the composite is acceptable.

Extending the drying time of the substrate cause an improvement on the composite bonded strength and fracture toughness of the joint although not fully recovered [ 44 , 154 ]. Thus, this is one of the areas that need a further attention. In addition to that fatigue behavior is still not well developed under the effect of pre-bond moisture. Thus, these are the areas that need a further attention. It is needed to elaborate this results in more fraction of moisture and provide a significant explanation for this. Nevertheless, it is necessary to have more experimental studies in order to justify or set the proper process parameter which link up the relationship between pre-bond moisture and bonded joint strength.

Post-bond moisture

The moisture absorption of the composite structures are mainly depends on the exposure condition such as: humidity, temperature, wind, UV radiation, thermal cycling, water and the exposure time. Moisture can ingress into the joint through diffusion into the bulk adhesive, composite laminate and wicking along the interface or capillary action into cracks and voids.

Several researchers [ 41 , 46 , 124 , 139 , 156 , 157 ] reported the reduction of bonded joint strength with effect of post-bond moisture. Weakening of bonding between the fiber and matrix and softening of matrix are the possible causes for the reduction in strength [ 124 , 139 , 156 , 157 ]. The strength reduction rate depends on the exposure time, exposure condition, type of adhesive material and adhered, which ultimately lead to final moisture content in the bonded joints. Jeoung et al. [ 158 ] noticed an increase in the failure strength (21%) compared to the dry joint at a moisture content of 1%. However, when the moisture content increased to 2.1% and 2.5%, the joint strength significantly decreased. It is believed that the composite joint strength increased at low moisture content due to the prevention of delamination by the compressive stress created between the plies of the adherend. The extent of the loss is dependent on the adhesive: adhesives cured at 175 °C give joints with lower strength losses than do adhesives cured at 120 °C [ 44 , 157 ]. Drying is the best suited treatment to recover the strength, However the full recovery was not achieved [ 34 ]. Drying at high temperature could improve the strength up to certain extent but blistering and some crack on the composite surface occur. Therefore, behavior of specific bonded systems exposed to various environments should be taken into account in durability design.

The performance of the composite bonded joints in the presence of moisture mainly depends on how particular adhesive and composite laminate behave when it’s subjected to the same moisture. In addition to that interface between adhesive-adherend and bonding manufacturing process such as co-curing, co-bonding, etc. also plays an important role [ 159 ]. So, complete performance data of the adhesive and the composite laminate should be in hand in the presence of moisture before selection for composite bonded joints.

• Hygrothermal

The combined effect of moisture and temperature is more severe than the adverse effect of each individual condition (temperature and moisture). Generally, moisture sensitivity (moisture absorption, desorption, and saturation) is more effective when the structure is exposed to elevated temperature.

Composite usually absorbs more water at high temperature and this is a common way to accelerate water absorption. It is clear from the Fig.  13 that the higher the temperature, the higher the moisture uptake rate and higher the saturation capacity [ 52 ]. Mijovic and Weinstein [ 160 ] found that absorbed water induced depression of glass transition temperature, T g in a Gr/Ep composite was strongly dependent on the temperature during the water absorption process. The magnitude of the reduction in T g under saturated conditions reflects the degree of resin plasticisation and water/resin interactions occurring in the material [ 125 ]. This effect is usually reversible when water is removed but exposure to high temperature can produce irreversible effects, which are attributed to the chemical degradation of the matrix and attack on the fiber/matrix interface [ 161 , 162 ]. The glass transition temperature under dry and saturated conditions is a critical property for composites as the maximum service temperature depends on it.

Moisture absorption kinetics of carbon/epoxy composites at 60 °C temperature and 95% RH, and at 70 °C temperature and 95% RH [ 52 ]

The mechanical performance of composite material is influenced by the hygrothermal effect. High temperature and absorbed moisture cause expansion and plasticization of the matrix and degradation of the fiber/matrix interfaces, which change residual stresses, elastic moduli and the critical stresses for damage such as transverse cracking and delamination [ 147 ]. The possible causes for the reduction in strength are the adverse effect of a higher degree of thermal stress at the higher temperature, matrix plasticization due to moisture and temperature, swelling and induced internal stresses, cracking/crazing due to both osmosis [ 163 , 164 , 165 , 166 , 167 , 168 ].

Adhesive (epoxy resin) usually absorbs more moisture as compared to the composite laminate and composite structure, but it absorbs even more at a particular temperature (elevated). The absorbed water molecules in an epoxy can exist in either the free or bound states [ 115 , 169 , 170 ]. Free water molecules act as a plasticizer, strongly reducing T g and the modulus of elasticity [ 171 ]. Usually, when the material is exposed in a hygrothermal environment the T g decreases and, therefore, the service temperature of the material changes. This modification in T g reflects the degree of resin plasticization and water/resin interactions occurring in the material [ 151 ]. Not only temperature and moisture but also exposure time and exposing temperature also decide the variation of glass transition temperature of epoxy resin [ 172 , 173 ]. Hence selection of adhesive material and its glass transition temperature should be notified before the application [ 158 ].

Limited research was carried out on hygrothermal effect on the bonded joints strength. Most of the researchers [ 41 , 157 , 158 , 174 ] reported the reduction in strength of ageing specimen (joints) at elevated temperature. However the strength of the pre-saturated joint up to 1.0% of the moisture content increase in both room and elevated temperature conditions. A decrease in strength was observed in the case of higher temperature and longer exposure time to humidity. The tensile strength and ILSS decrease when the material has been exposed to moisture and tested at elevated temperature. But, no significant difference was reported for strength in between autoclave and vacuum-cured materials. This result supports the feasibility of scarf joint repairs with pre-cured or cocured patches under vacuum curing conditions in field-level facilities. Therefore, repairs with vacuum pre-cured or vacuum co-cured patches requiring less equipments seem to be a serious potential alternative to the composite patch repair requiring autoclave conditions which might be only available at depot level maintenance centers [ 96 ].

To summarize, the individual effect of moisture and temperature on the mechanical properties of adhesive material and joints is well understood, but there is a still a lack if systematic ageing conditions to clearly identify the combined effect of each environmental parameter.

Finite element method

An increasing complexity in geometry and material non-linearity of composite repair bonded joints makes difficult to obtain an overall governing equation. In addition to that, incorporation of the environmental parameters i.e. moisture and temperature in the analysis makes more complex the mathematical formulations. However, the experiments are often time consuming and costly. Therefore, the finite element analysis can be employed to overcome the limitations of the analytical methods.

Several researchers [ 6 , 10 , 11 , 13 , 175 , 176 , 177 , 178 ] successfully used finite element and analytical tools to perform a broad geometric and material parametric studies to optimise the parameters for maximum repair joint performance. Figure  14 shows the main geometrical parameters such as scarf angle, number of steps, patch thickness, adhesive thickness, overlap length, doubler plate, stacking sequence etc. of scarf and stepped lap repair joint. Selection of failure criterion is an important parameter for finite element analysis of the composite bonded joints. For linear elastic analysis, peal stress and shear stress value were considered as a failure criterion performance (quality indicator), where the adhesive behavior assumed to be elastic. When the adhesive behaviour became non-linear, the maximum shear strain of the adhesive layers was used to assess the joint strength. One problem with the allowable stress or allowable strain criterion is the mesh dependent singularity at the tip of the crack (geometric singularity), as well as the singularity at the intersection of each ply and the adhesive (stiffness mismatch) [ 17 , 179 ].

Design parameters of a scarf repair, b stepped lap repair

Recently, a cohesive zone model (CZM) modelling methodology has been shown to be a versatile approach to predict the durability of adhesively bonded joints exposed to humid environments [ 68 , 164 , 180 , 181 , 182 , 183 ]. The accurate prediction of failure behaviour should be correctly implemented using a traction–separation law which includes triangular, trapezoidal and exponential shape [ 184 , 185 ]. The parameters that principally define the traction–separation response are the cohesive fracture energy and the critical traction of the adhesive in each fracture mode. A proper selection of traction–separation law behavior is important. For example, a trapezoidal law predict more accurate for temperature variation in the joint [ 68 , 183 ]. As the moisture concentration adversely influences the cohesive properties, moisture-dependent cohesive properties are required to accurately predict the failure behavior of a saturated or unsaturated adhesively bonded joint using the cohesive zone approach.

Incorporation of fracture data from the ageing test into a fracture prediction methodology to enable the prediction of real closed joints is a real issue and time taking also, hence it is essential to use testing techniques that accelerate the ageing. To accelerate the ageing the open-faced method has shown a great promise in significantly reducing the time and cost of fracture tests. However, the challenge is how to incorporate the fracture data from accelerated ageing test into a fracture prediction methodology to enable the prediction of real closed joints. Ameli et al. [ 186 ] successfully assessed the applicability of the open-faced technique to predict the durability of closed double cantilever beam (CDCB) specimens. A framework for the assessment of the applicability of the open faced technique to the prediction of the durability of closed DCB (CDCB) joints is shown in Fig.  15 [ 187 ]. The significance of this framework is the ability to remarkably reduce the exposure time by using the open-faced technique and to incorporate the spatial variation of degradation in the closed joint with the aid of the 3D finite element model [ 187 ].

Framework for the FE prediction and validation of fracture toughness in environmentally degraded closed adhesive joints [ 187 ]

The lifetime of bonded joints is difficult to model accurately and their long term performance cannot easily and reliably be predicted, especially under the combined effect of an aggressive environment and mechanical loading. In addition to that, incorporation of manufacturing process of the bonded repair on its stress state in cohesive zone model is needed, as this parameters shows positive response on bonded repair performance. The problem of durability of adhesive joints to hostile environments has become the main challenge for researchers in this area. This mechanism can however be included by defining the delamination strength for the composite with a mode dependent CZM parameters.

Conclusions

Important concerns are critically expressed here regarding the environmental variants (moisture, temperature, humidity etc.) on mechanical performance of composite repair bonded joints. In recent years, many developments have been made by researchers to improve the environmental resistance of the composite structures such as new advanced composite and adhesive material, curing method, manufacturing bonded joints method, etc. Hence, there is strong need for improving the current composite repair subjected to environmental issues such as moisture, temperature etc. for reliable and repeatable repairs. In this review, several scientific challenges and opportunities have been identified in order to develop more durable and cost-effective composite bonded repair technologies with short repair cycle:

There is no generalised trend with respect to the effect of moisture and temperature on the bonded joint as it depends on a number of factors: such as curing temperature, curing method, adhesive and composite laminate material. Hence, an urgent need to assess and evaluate the behavior of advanced composite laminate and adhesive material under high and low temperature as well under different moisture conditions in order to utilize the full capability of the material for bonded repair joints. Advanced structural adhesives and composite material, could offer opportunities to enhance strength and long-term durability of bonded repairs.

Time required to fabricate bonded repair mainly depends on drying of composite before repair bonding and curing the same repair joints, could significantly influence the associated economical aspects. The material system that can cured at low temperature with short cycle but should have higher glass transition temperature could be a good for bonded repairs. A complete drying of composite is in current practice of composite repair, but it is not necessary always as deduced by researchers. So curing at low temperature and not complete drying, both help to reduce the repair time which impact on huge economical aspect.

Performance of composite repair can be improved by implementing new methods: such as curing by vacuum method which produce a good quality repair with low bondline void as similar to the autoclave curing method, manufacturing by co-bonded method joints, which absorb less moisture compare to the co-cured bonded joints method. There is need to work on this aspect and plan for more tests and confirm assurance for the better composite repair bonded joints.

The available studies focusing on the effect of moisture and temperature on the mechanical behavior of adhesively bonded joints still have considerable differences in terms of the adherend and adhesive material properties, the material processing methods, adhesive curing temperature and specimen configurations. Thus it is important to have the pre-knowledge (such as curing temperature, glass transition temperature, moisture absorption–desorption limit, swelling, thermal expansion, etc.) of the adhesive and composite behavior at the specified temperature and moisture level over which structure will expose during service period for the best used of material to obtained a better composite repair joints.

Limited studies were carried out on the effect of hygrothermal (moisture and temperature) on the composite bonded joints and it is highly demand for this study as the combined effect is more sever than individual condition.

Aerospace industry demand for lower frequency of repair and maintenance of the composite structure and this can be possible by introducing the self healing materials which can help to improve the durability of the structure. Also composite bonded structure should easily disbond without damaging the structure, then it can be used for reuse and recycle. Both these aspect should be implemented in the current scenario in order to reduce the frequency of the maintenance and easily separate without damaging the parent structure at the time of repair.

Finite element method is well developed numerical tool and used to optimise the geometry and material parameter of repair joint for better performance of the structure. Failure criterion of the composite bonded joints and incorporation of moisture and temperature parameter is the main constraint in scarf and stepped lap joints. Cohesive zone model successfully incorporate the environmental issue on the bonded joints and analyse the joints under the influence of moisture and temperature. Still long term durability is a major concern, as it is difficult to predict accurate environmental behavior of the joints. Open face specimen technique introduced accelerated ageing which help to reduce the exposure time. Open face technique offer opportunities for developing accurate prediction of joint behavior for long term using cohesive zone modeling to any adhesive system that exhibits nonuniform degradation.

Abbreviations

glass transition temperature

cured in place

glass fiber reinforced polymer

carbon fiber reinforced polymer

polymer matrix composites

fiber reinforced polymer

coefficient of thermal expansion

relative humidity

fracture toughness under mode I loading

cohesive zone model

matrix deformation

fiber bridging

fiber fracture

fiber-matrix interfacial debonding

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Budhe, S., Banea, M.D. & de Barros, S. Bonded repair of composite structures in aerospace application: a review on environmental issues. Appl Adhes Sci 6 , 3 (2018). https://doi.org/10.1186/s40563-018-0104-5

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This study aimed to empirically examine what effects confidence, social, and economic benefit factors have on continuous relationship orientation through the mediation of service trust, service satisfaction, and customer engagement factors in the auto maintenance and repair service sector. This study carried out a questionnaire survey with 319 customers using auto maintenance and repair service and verified hypotheses. As a result of the analysis, the confidence and social benefits of auto maintenance and repair service affected service trust, while the confidence and economic benefits affected service satisfaction. Service trust did not affect customer engagement or long-term relationship continuity but affected them when it mediated service satisfaction. Consequently, it was revealed that confidence benefit should be consolidated and that professionalism or service quality excellence in maintenance or repair becomes the most important factors to produce customer engagement or long-term relationship continuity in the auto maintenance and repair service. Although it is vital to improve trust or service, it is confirmed that a relationship can be maintained only if the auto maintenance or repair service is satisfactory.

1. Introduction

Most service companies offer new services and benefits to continuously maintain relationships with existing customers or create higher customer satisfaction according to the individualization of customer needs and differentiated service demand increase. Since service has intangible characteristics, broader customer contacts are made in the process of meeting customer expectations, and interactions with customers produce a positive impression or trust, which works as a key factor for relationship continuity. In the end, relationship benefits revealed through interactions between companies and customers play a pivotal role in retaining customers. The after-sales service, one of the methods for achieving customer satisfaction in auto maintenance and repair service, is most valuable, and efficient after-sales service becomes the highest priority of auto maintenance and repair service companies [ 1 ]. However, customers can personally manage auto maintenance and repair nowadays, including accident history and consumable parts replacement cycle based on smartphones, through new systems improving auto maintenance and repair management as advanced technologies are applied. Furthermore, general visit-management services, such as car wash, light maintenance, and repair and consumable parts replacement by visiting, due to platform invigoration, have continuously developed.

In the changed maintenance and repair service market environment, the need for after-sales service satisfaction enhancement, differentiated service offering for customer retainment, and customer relationship maintenance strategy increases. For example, BMW additionally offers the BMW Service Inclusive (BSI), warranting consumable parts replacement and regular inspection within 100,000 km for five years, in addition to basic warranty service. Toyota renders efforts to diversify customer service through such assistances as the “Express Service” by which inspection can be finished within an hour. Meanwhile, Lexus offers a 24-h emergency mobilization service and provides a female lounge strictly for female customers. Hyundai Motors and Kia Motors push ahead with an excessive maintenance and repair prevention program to compensate up to 300% of excessive charge if an excessive maintenance and repair service is presented to the customer service center after the excessive service, and when it is judged so after an expert’s investigation.

Such efforts of the companies in the auto maintenance and repair service show that existing customer retention and relationship consolidation is a more important task, rather than securing new customers, due to a rapid change of technology and market environment and an increase in customer needs and service expectation level. As previous studies [ 2 , 3 ] assert that income can increase from 25% to 85% if customer churn rate is reduced by 5%, the retention of existing customers and relationship consolidation through the establishment of customer relationships become a key marketing strategy direction to auto maintenance and repair service companies. For their steady earnings creation and efficient management, it is important to strengthen long-term relationships with customers, and two-way communication and close relationship establishment are important because companies and customers have a win-win relationship for mutual value, and not a mutually competing relationship [ 4 ]. One of the long-term strategies forming, maintaining, and consolidating relationships between companies and customers is relationship marketing. If a company has customers for the long-term, the company’s earnings can be assured to some degree. Relationship marketing brings about positive results, including customer participation and efficient customer responses [ 5 ].

Even though various studies on relationship benefits, relationship quality, and customer retention between companies and customers have been actively performed [ 6 ], few studies on relationship benefits or relationship quality between auto maintenance and repair service companies and customers in which relationship continuity with customers has important industrial characteristics have been carried out. In this context, this study purposed an empirical analysis of the effects of the relationship benefits on long-term relationship establishment in customers, using perception to auto maintenance and repair service with meditated effect of service trust, repair service, and customer engagement attributes. In the auto maintenance and repair service process, a service provider’s role is important, in addition to service quality, and there is a need to induce customers’ active re-purchase and intention to orally pass down the service provider through customers’ positive feelings and experiences at the service contact point. From this aspect, this study presented specific implications for service process improvement and marketing strategy within the auto maintenance and repair service industry.

2. Theoretical Background and Hypothesis Development

2.1. relationship benefits, service trust, and service satisfaction.

In the service process, a service provider’s role is essential, in addition to service quality. At the service contact point, customers’ positive feelings on and experiences with service providers can be connected to their re-purchase and positive intention to pass down feedback on the service providers [ 7 ]. Reichheld et al. [ 8 ] asserted that companies can increase 100% of their profits by maintaining more than 5% of their customers. Customer churn can be connected to corporate profit increase through long-term relationship retention with customers. From this perspective, relationship benefits mean the benefits that a company can offer to customers if the company’s understanding of the customers is enhanced once a firm’s relationship with customers is maintained for a certain period of time through relationship development. Gwinner et al. [ 9 ] defined all types of benefits offered to customers as the concept of relationship benefits. Palmatier et al. [ 10 ] insisted that relationship benefits are one of the key strategies to ensure the service company’s profitability and competitive advantage. Companies need to maintain a relationship with customers for a certain period of time, and their understanding of customers is enhanced through the process, where the company can finally offer the benefits that customers want [ 11 ].

In many studies, the social, psychological, and individualized relationship benefits of Quach et al. [ 12 ] are slightly differently categorized by researchers. Reynolds and Beatty [ 13 ] categorize relationship benefits into confidence, social, and special treatment benefits, while Ulaga [ 14 ] classifies relationship benefits into benefits, procedures, and operational benefits. Conze et al. [ 15 ] define relationship benefits as psychological, social, special treatment, and diversity-pursuing benefits. Reimer and Kuehn [ 16 ] performed a study with economic, social, psychological, special treatment, and information benefits. This study was performed with confidence and social benefits existing between the service providers and customers and with economic benefits that become the most basic in relationship benefits in consideration of auto maintenance and repair service characteristics with low customer contribution to the limitation and function of the special treatment category. Confidence benefit reduces worries and makes customers feel comfortable, as it can predict achievement with the feeling of belief in service providers [ 17 ]. Social benefit makes customers feel an affinity towards the service providers, enabling social relationship [ 18 ]. Lastly, economic benefit is what customers receive based on time and cost savings or functional convenience [ 19 ].

By continuously providing relationship benefits based on customer preference, relationship benefits form a significant relationship quality with customers [ 20 ]. Darkhantuya [ 21 ] said that relationship benefits have a partially significant effect on customer satisfaction, and Kang and Kim [ 22 ] also reported that relationship benefits have a partially significant effect on customer satisfaction. The formation and retention of long-term relationships with customers create a significant effect on relationship quality, customer satisfaction, and customer loyalty through strong service [ 23 ]. Consequently, relationship benefits are revealed among trust, commitment, and satisfaction [ 24 ]. This study tried to grasp the association between service relationship benefits and relationship quality with two factors, that is, service satisfaction and service trust formed in customer relationship among relationship quality factors. This study set the following hypotheses on customer trust on and satisfaction with auto maintenance and repair service and with regard to confidence, social, and economic benefit factors:

Confidence benefit of the relationship benefits on auto maintenance and repair service will have a positive effect on service trust.

Social benefit of the relationship benefits on auto maintenance and repair service will have a positive effect on service trust.

Economic benefit of the relationship benefits on auto maintenance and repair service will have a positive effect on service trust.

Confidence benefit of the relationship benefits on auto maintenance and repair service will have a positive effect on service satisfaction.

Social benefit of the relationship benefits on auto maintenance and repair service will have a positive effect on service satisfaction.

Economic benefit of the relationship benefits on auto maintenance and repair service will have a positive effect on service satisfaction.

2.2. Service Trust, Service Satisfaction, and Customer Engagement

As for studies related with relationship benefits in a variety of fields that targeted service companies, papers researching the effects on relationship achievements such as loyalty and passing down feedback through relationship quality, including customer satisfaction, trust, and commitment are the mainstream research trend [ 25 ]. Crosby et al. [ 26 ] presented relationship quality as the degree of interactions between sellers and purchasers and reported that relationship quality consists of trust and satisfaction. Mohr and Spekman [ 27 ] reported that a successful partnership is composed of commitment, trust, coordination, participation, communication quality, and common problem resolution. Storbacka et al. [ 28 ] presented a dynamic model of relationship quality and asserted relationship quality as satisfaction, communication, commitment, and solidarity. Harris and Ezeh [ 29 ] conceptualized relationship quality into three structures composed of customer trust, achievement of work required in relation to work performance, and customer commitment to a corporate relationship. Van Doorn et al. [ 30 ] defined relationship quality as the suitability level of relationship in meeting customer needs, which is similar to the concept of product quality.

As customer service experience or participation changes vigorously and actively, the concept of customer engagement emerges beyond commitment. Customer engagement is a customer’s active participation toward companies as derived from motive stimulation beyond purchase [ 31 ]. Brodie et al. [ 32 ] defined customer engagement as a psychological state generated from mutually and jointly creative customer experience with companies in a relationship between companies and customers. Customer engagement consists of interest, interaction, and commitment as it is revealed as an interaction between customers. And it reveals oral passing down activity, posting on blogs, co-participation, and customer evaluation on experienced goods or services [ 33 ].

Based on previous studies, customers satisfied with the current auto maintenance and repair service can change their selection if there are products or services that offer higher satisfaction [ 34 ]. This study tried to examine service trust, which is a psychological belief state indicated in the exchange relationship between customers and car maintenance and repair centers. Moreover, this study designed a hypothesis that customer’s trust in auto maintenance and repair service will have a positive effect on satisfaction. In addition, this study designed and proved the following hypotheses from the following aspects: given that customer interest in auto maintenance and repair service increases and market environment changes with higher active participation, customers will show their emotional and voluntary behaviors toward companies based on a fair relationship with companies in the auto maintenance and repair service industry [ 35 , 36 ].

Trust in auto maintenance and repair service will have a positive effect on customer satisfaction with the service.

Trust in auto maintenance and repair service will have a positive effect on customer engagement.

Satisfaction with auto maintenance and repair service will have a positive effect on customer engagement.

2.3. Service Trust, Service Satisfaction, and Long-Term Relationship Orientation

Long-term relationship orientation can be a firm’s prime goal to maintain relationships with existing customers for a long time and prevent churn to other companies [ 37 ]. Previous studies on long-term relationship orientation are discussed in various approaches. From mutual benefit between transaction parties, Kelley and Thibaut [ 38 ] said that common achievements of transaction parties including suppliers are the mutually dependent common activity results over a long period of time. Gwinner et al. [ 9 ] reported that purchasers reduce transaction experiences or future benefit’s uncertainty by forming a long-term bond with suppliers to obtain specific benefits that cannot be obtained from a short-term transaction relationship; therefore, long-term relationship orientation between purchasers and suppliers is sought.

Long-term relationship orientation is based on how relational the existing transactions have been, rather than on the period of forming relationships between customers and companies beyond a simple, repeated behavioral purchasing. Johnson et al. [ 39 ] explained that both parties forming a transaction relationship to meet end-user needs assert their own activities from a long-term perspective, while they explained a partnership-like, thinking-dominating transaction relationship by which one party’s success can be decided by the other party as long-term relationship orientation. Long-term relationship orientation is a concept encompassing relationship continuity and interdependence between companies and consumers, and it is the concept containing attitude and behavioral intention. Therefore, it can include repeated purchasing behaviors, an intention to pass down feedback, and an intention to continue the relationship [ 40 ].

The long-term relationship orientation is revealed as a consumer’s conscious judgment or evaluation result and is affected by perceived psychological factors. Consequently, it is linked with factors like customer engagement affecting customer satisfaction with service, trust in products, or services, and customer’s active relationship improvement according to experiences as mentioned in previous studies [ 41 , 42 , 43 , 44 ]. Flavián et al. [ 45 ] asserted each party’s activities from the long-term perspective between the parties in a transaction relationship to meet customer needs, stating that both parties should perceive the other party as in a partner relationship. It means that factors such as trust, dependence, environmental uncertainty, reputation, and satisfaction affect long-term relationship orientation. Lai [ 46 ] said that trust in and satisfaction with salespersons are major factors that consumers consider when forming a continuous relationship with sellers.

And relationship quality improvement, including satisfaction and trust between companies and customers in service sales and experience activities between companies in various service industries and customers, has a significant effect on long-term relationship orientation [ 47 , 48 , 49 ]. Consequently, service trust and service satisfaction as relationship qualities regarding auto maintenance and repair service felt by customers will have a significant effect on long-term relationship orientation.

Trust in auto maintenance and repair service will have a positive effect on long-term relationship orientation.

Satisfaction with auto maintenance and repair service will have a positive effect on long-term relationship orientation.

Because customer engagement is a customer’s relationship-forming behavior to create and maintain a relationship between companies and customers through a customer’s voluntary and positive participation, such customer behavior can be revealed as long-term relationship orientation with companies [ 50 , 51 ]. This study designed a hypothesis that customer engagement in auto maintenance and repair service will have an effect on long-term relationship orientation with customers.

Customer engagement improvement on auto maintenance and repair service will have a positive effect on long-term relationship orientation.

3. Research Methods

3.1. research model.

Through the hypotheses drawn based on previous studies, a study model as shown in Figure 1 was designed. Confidence, social, and economic benefits, which can be defined as relationship benefits in auto maintenance and repair service, were set as independent variables. As parameters, service trust and service satisfaction were set; thus, whether the relationship benefits had effects on the dependent variables, customer engagement, or long-term relationship orientation through the mediation of two factors, which were service trust and service satisfaction, was set. This study set each path composition to check whether service trust has the effect on service satisfaction in the auto maintenance and repair service customer group and to check whether customer engagement has an effect on long-term relation orientation.

Research model.

3.2. Measurement Variables

For data collection to analyze the model, a questionnaire survey was carried out; the questions were composed through previous studies, as shown in Table 1 , and manipulative variables of the questionnaire components to be composed of questions were defined. The variables defined as above consisted of questions as shown in Table 1 and were investigated with a 5-point Likert scale (1 = strongly disagree, 2 = disagree, 3 = no opinion, 4 = disagree, 5 = strongly agree). Three questions were composed, each for confidence benefit and social benefit based on the studies of Gwinner et al. [ 9 ], Reynolds and Beatty [ 13 ], and Henning-Thurau et al. [ 25 ]. Likewise, there were three questions for the economic benefit based on the studies of Yen and Gwinner [ 17 ] and Koritos et al. [ 19 ]. Two questions were composed, each for service trust and service satisfaction based on a study of Sirdeshmukh et al. [ 52 ] and the studies of De Wulf et al. [ 53 ] and Eggert and Ulaga [ 41 ], respectively. For customer engagement, two questions were composed in order to be passed down orally and with an intention to participate for improvement based on the studies of Brodie et al. [ 32 ] and So et al. [ 54 ]. Lastly, three questions were composed for long-term relationship orientation based on the studies of Ganesan [ 55 ] and Jahanshahi et al. [ 56 ]. The item “Not anxious when using the service” in confidence benefit and the item “Receive much discount” in economic benefit were excluded in this study as they were not significant as a result of the analyses of measurement model trust and convergent validity.

Measurement variables and items.

3.3. Survey and Analytic Methods

The questionnaire survey targeted customers having experiences of using auto repair centers. In consideration of car use and the number of maintenance and repair service, the customers using auto maintenance and repair service in Seoul and major cities in Gyeonggi Province in South Korea were selected. The copies of the questionnaire that were drawn up with Google Survey for 30 days from July 1 to July 30, 2019, were distributed and collected through email and SNS (social network sites). Finally, 464 questionnaire responses were collected, and a total of 319 were analyzed, except for 145 insincerely responded to questionnaire copies. For data analysis, SPSS 24.0 was used and basic data reliability and validity were examined through demographic characteristics, descriptive statistics, and exploratory factor analyses. The factor analysis and model verification, along with path analysis for structural equation model analysis, were analyzed using AMOS 25.0. For the mediation effect verification of service trust and satisfaction, a bootstrapping technique in line with the previous study guide of Gallagher et al. (2008) was used.

4.1. Demographic Information of the Data

As a result of carrying out a questionnaire survey targeting auto maintenance and repair service-experiencing customers, the demographic analysis result for 319 customers is shown in Table 2 . There were over three times more males (79.3%) than females (20.7%). As for age, the customers in their 40s, 30s, and 50s were 33.2%, 29.2%, and 26%, respectively, and those in their 40s showed the highest experience ratio of car repair centers. Concerning customers’ occupation categorization, service industry showed 25.7% and manufacture/production showed 19.1%, while others took up a high ratio, which shows that the customers were distributed to various occupation groups. 93.4% of the customers visited car repair centers for the maintenance and repair of their cars, with the interest in car maintenance and repair being as follows: very high showing 52.4% and moderate being 40.4%, which implies chiefly high interest.

Demographics of survey participants.

4.2. Analysis Results of Reliability and Validity

For the analysis of the reliability and validity of the structural equation measurement model, it can be said that internal consistency reliability was ensured if the composite reliability index was 0.7 or higher [ 57 ]. Convergent validity is evaluated with factor loading, Cronbach’s α, and composite reliability index, and it can be said that convergent validity is ensured if factor loading is 0.4 or more, Cronbach’s α is 0.6 or more, and statistical significance is shown [ 58 ]. In line with the above criteria, factor loading was 0.645–0.851, all were more than 0.6, and thus they were good, whereas internal consistency reliability ensured significance with 0.759–0.855 (composite reliability). Because the t value of all was 6.0 or more, statistical significance was confirmed. The AVE (average variance extracted) value was 0.616–0.720 and Cronbach’s α value was 0.713–0.789; therefore, convergent validity was ensured. As a result of analysis on the measurement model fit, χ 2 (p) was 76.066 and χ 2 /degree of freedom was 1.729. Goodness-of-Fit-Index (GFI) value was 0.968, Adjusted Goodness-of-Fit Index (AGFI) was 0.944, Normal Fit Index (NFI) was 0.961, and Root Mean Square Error of Approximation (RMSEA) was 0.043. The composition values of the measurement model fix were excellent (see Table 3 ).

Analysis of trust and convergent validity of the measurement model.

(1) Measurement model fit: χ 2 (df) 240.81, p 0.0 DF 98, χ 2 /degree of freedom 2.457, Root Mean Square Residual(RMR) 0.400, Goodness-of-Fit Index (GFI) 0.919, Adjusted Goodness-of-Fit Index (AGFI) 0.874, Normal Fit Index (NFI) 0.962, Tucker Lewis Index (TLI )0.968, Comparative Fit Index (CFI) 0.977, Root Mean Square Error of Approximation (RMSEA) 0.068. (2) * p < 0.05, ** p < 0.01, *** p < 0.001.

In the case of correlation analysis, as shown in Table 4 , it can be said that discriminant validity is ensured among potential variables if the square root value of AVE calculated between potential variables in line with the criteria presented by Gallagher et al. [ 59 ] is larger than each potential variable’s correlation coefficient. As a result of the analysis on the AVE values and correlation coefficients among potential variables in Table 4 , each potential variable’s AVE square root value was larger than the correlation coefficient among potential variables, whereas the correlation coefficient values were 0.7 or more and were significant; therefore, discriminant validity was ensured.

Discriminant validity.

* p < 0.05, ** p < 0.01, *** p < 0.001.

4.3. Analysis Results of Structural Model

As shown in Table 5 , prior to the path analysis, χ 2 (p) was 291.571, χ 2 /degree of freedom was 2.804, GFI value was 0.900, namely 0.9 or more, whereas AGFI was 0.853, NFI 0.954, and RMSEA 0.075, and goodness-of-fit component values were excellent, and therefore the goodness of fit was significant. CFI representing a model’s explanation power was 0.970, TLI judging the explanation power of the structural model was 0.960, and all were 0.9 or more, and thus the basic model was analyzed to be very fitting. As a result of the path analysis through the structural equation modeling analysis, three hypotheses out of 12 hypotheses were rejected.

Hypotheses verification.

(1) Structural model fit: χ 2 (df) 291.571, p 0.0, DF 104, χ 2 /degree of freedom 2.804, RMR 0.061, GFI 0.900, AGFI 0.853, NFI 0.954, TLI 0.960, CFI 0.970, RMSEA 0.075. (2) * p < 0.05, ** p < 0.01, *** p < 0.001.

Table 6 shows the direct and indirect effects analysis result. The confidence benefit (10.952) and social benefit (3.331) of the service relationship benefit factors showed a positive effect on service trust, and thus the hypothesis was accepted. However, the economic benefit did not have an effect on service trust. The confidence benefit (5.104) and economic benefit (2.449) had a positive effect on service satisfaction, but the social benefit factor rejected the hypothesis. Meanwhile, service trust did not have an effect on customer engagement or long-term relationship orientation. In contrast with this, service satisfaction had a positive effect on customer engagement (4.041) and long-term relationship orientation (3.090); thus, the hypothesis was accepted. It was confirmed that service trust had a positive effect on service satisfaction (6.048) in auto maintenance and repair service as shown in previous studies [ 60 , 61 ] and that customer engagement had a positive effect on long-term relationship orientation (7.764), therefore rendering the hypothesis acceptable.

Direct and indirect effects analysis result.

Note: * p < 0.05, ** p < 0.01, *** p < 0.001.

As a result of mediation effect verification on service trust and service satisfaction factors using the bootstrapping technique, the service trust mediated confidence benefit (0.285**) and social benefit (0.114**) but did not mediate economic benefit. Specifically, there is a need to consolidate confidence and social benefits rather than economic benefits to enhance satisfaction through service trust. The service trust (0.233*), confidence benefit (0.536**), social benefit (0.156**), and economic benefit (0.139*) that used service satisfaction on customer engagement as mediation showed indirect effects, thus confirming to work as parameters. The indirect effects of all variables on long-term relationship benefit also showed significant difference and, therefore, all factors including service satisfaction and service trust were confirmed to show mediation effects. This reveals that service trust can show effects through the mediation of service satisfaction, although service trust cannot directly affect customer engagement and long-term relationship organization.

5. Conclusions

This study aimed to verify the effect relationship between service relationship benefits and service trust, service satisfaction, customer engagement, and long-term relationship orientation by targeting auto maintenance and repair service customers in order to seek methods to retain customers and enhance relationship continuity through the customer relationship marketing invigoration of auto maintenance and repair companies. As a result of the analysis, three conclusions were drawn. First, the economic benefit out of the confidence benefit, social benefit, and economic benefit factors, which were the relationship benefit factors of auto maintenance and repair service, did not have an effect on customers’ service trust. The customers’ service satisfaction was affected through the economic benefit in auto maintenance and repair service as previous studies [ 57 , 62 ] presented economic benefit such as prices or discount rates as an important factor to service consumption behaviors of customers. Furthermore, the analysis result was confirmed that service trust was affected by social benefits, rather than by economic or confidence benefits. It means that the social benefit of service relationship in auto maintenance and repair service is significant to lead a strong relationship with customers.

Second, the social benefit of auto maintenance and repair service had an effect on service trust but did not have an effect on service satisfaction. Through the result, it was confirmed that affinity or relationship with repair center workers affected trust formation, but it did not directly affect the service satisfaction with auto repair or maintenance result, and that such direct factors as service quality or cost-effectiveness, namely economic and confidence benefits, were more important. It opposed to the previous researches identified the relationship benefits have a positive effect on service satisfaction [ 60 , 61 ]. It means that the customer’s behavior toward the service center and the relationship with workers in the auto maintenance and repair service sector should be objective and reasonable rather than other service sectors.

Third, as a result of a mediation effect analysis, service satisfaction showed significant mediation effects on customer engagement and long-term relationship orientation with regard to service relationship benefit factors. Meanwhile, service trust did not show any direct mediation effect but showed the mediation effect through double mediation on service satisfaction. This means that auto repair centers need to concentrate on service satisfaction to directly affect customers’ behavior interest or long-term relationship formation, although service trust is important to the customers using auto maintenance and repair service. Through the result, it was confirmed that a strategy to improve service satisfaction based on trust rather than concentration on service trust establishment for customer management is more important to the auto repair centers, unlike in the previous studies [ 63 , 64 , 65 , 66 ], asserting that establishing loyalty and transaction continuity by gaining service trust can be a positive customer management strategy to general service companies.

Consequently, it was verified that the consolidation of confidence benefit, namely maintenance and repair professionalism and expertise and quality excellence on service result, was a highly important factor that induced customer trust and satisfaction, and thus long-term relationship continuity in auto maintenance and repair service. This was a characteristic that the auto maintenance and repair industry had, which showed the importance of maintenance and repair works for relationship continuity, although social benefits or trust formation was valuable according to the characteristics of service attributes associated with safety or management professionalism, unlike customer activity or experience-oriented services such as restaurant, banking, and tourism.

Auto maintenance and repair service companies need to emphasize maintenance and repair service professionalism and excellence in building up interactions with customers or a communication strategy for long-term customer relationship marketing. They also need to seek service differentiation by establishing marketing contents linked with auto management and maintenance and repair technological capabilities and systems. From this aspect, this study has significance in that it specifically presented a relationship marketing strategy direction by examining various effect relationships such as service trust, satisfaction, and customer engagement, as well as relationship benefit factors on auto maintenance and repair service beyond service quality and satisfaction factors dealt with in the previous studies.

Nonetheless, this study has the following research limitations. First, this study targeted auto maintenance and repair service-experiencing customers within South Korea and, therefore, there is a research limitation that the study result cannot be generalized as maintenance and repair service relationship benefit characteristics since the Korean auto maintenance and repair service market and customer characteristics have been reflected. A further study needs to research this by expanding the target market to the Asian, American, and European areas, thus drawing the relationship benefits and customer behavior of auto maintenance and repair service targeting the global market, and comparatively research according to each continent’s characteristics.

Second, this study has a research limitation in that it did not apply the relationship benefit factors that the auto maintenance and repair service had by applying service companies’ relationship benefit factors to the auto maintenance and repair service companies. A further study needs to examine more specific relationships and customer behavior factors based on the research in order to draw and define unique relationship factors within the repair centers and customers in the auto maintenance and repair service industry. Furthermore, future research should investigate the direct effect between the relationship benefits and long-term relationship orientation even if this research did not suggest the hypothesis of it.

Lastly, various services exist and have been segmented in the auto maintenance and repair service including test driving upon car purchase, maintenance/repair and warranty repair according to car use, used car disposition and inspection, scrap car handling, and parts purchase. Therefore, research needs to be developed by considering the diversity of the auto maintenance and repair service process and segmenting auto repair company size, facility conditions, and customer’s service-experience level.

Acknowledgments

This research was supported by aSSIST (Seoul School of Integrated Sciences and Technologies).

Author Contributions

Funding acquisition, J.H.; methodology, S.O.; resources, J.H.; supervision, B.K.; writing—original draft, B.K. and J.H.; writing—review and editing, B.K. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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ROS-responsive hydrogels with spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs for the repair of MRSA-infected wounds

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Bowen Qiao, Jiaxin Wang, Lipeng Qiao, Aziz Maleki, Yongping Liang, Baolin Guo, ROS-responsive hydrogels with spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs for the repair of MRSA-infected wounds, Regenerative Biomaterials , Volume 11, 2024, rbad110, https://doi.org/10.1093/rb/rbad110

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For the treatment of MRSA-infected wounds, the spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs is a promising strategy. In this study, ROS-responsive HA-PBA/PVA (HPA) hydrogel was prepared by phenylborate ester bond cross-linking between hyaluronic acid-grafted 3-amino phenylboronic acid (HA-PBA) and polyvinyl alcohol (PVA) to achieve spatiotemporally controlled release of two kinds of drug to treat MRSA-infected wound. The hydrophilic antibiotic moxifloxacin (M) was directly loaded in the hydrogel. And hydrophobic curcumin (Cur) with anti-inflammatory function was first mixed with Pluronic F127 (PF) to form Cur-encapsulated PF micelles (Cur-PF), and then loaded into the HPA hydrogel. Due to the different hydrophilic and hydrophobic nature of moxifloxacin and Cur and their different existing forms in the HPA hydrogel, the final HPA/M&Cur-PF hydrogel can achieve different spatiotemporally sequential delivery of the two drugs. In addition, the swelling, degradation, self-healing, antibacterial, anti-inflammatory, antioxidant property, and biocompatibility of hydrogels were tested. Finally, in the MRSA-infected mouse skin wound, the hydrogel-treated group showed faster wound closure, less inflammation and more collagen deposition. Immunofluorescence experiments further confirmed that the hydrogel promoted better repair by reducing inflammation (TNF-α) and promoting vascular (VEGF) regeneration. In conclusion, this HPA/M&Cur-PF hydrogel that can spatiotemporally sequential deliver antibacterial and anti-inflammatory drugs showed great potential for the repair of MRSA-infected skin wounds.

The skin separates the internal environment of the human body from the external environment and plays a crucial role in the human body [ 1 , 2 ]. However, skin is very vulnerable to injury, which includes external factors (surgery, pressure, burns and cuts, etc.) and pathological factors (diabetes or vascular disease, etc.) [ 3 ]. These injuries can cause gaps in the protective barrier of the skin, allowing pathogens such as bacteria to attack the human body through gaps. Research showed that methicillin-resistant Staphylococcus aureus (MRSA) can exist in 7–30% of wounds [ 4 ], and MRSA may spread into the blood, even endanger life. Because MRSA is an antibiotic-resistant pathogen that can cause multiple serious infections, research by the World Health Organization have shown that the mortality rate of MRSA-infected patients is 64% higher than that of other infected patients [ 5 ]. Therefore, effective treatment strategies for MRSA infection are particularly important for people’s lives and health.

At present, there are many strategies for the treatment of MRSA-infected wounds, such as antibiotics, bacteriophages and nanomedicine platforms [ 6 , 7 ]. Among numerous treatment methods, the use of antibiotics that can kill drug-resistant bacteria can directly and effectively treat MRSA infection, but the unreasonable use of drug doses gradually reduces the therapeutic effect of antibiotics, and even forms the antibiotic resistance [ 8 , 9 ]. Therefore, designing and developing better biocarrier to control antibiotics release is a mainstream direction for the treatment of MRSA infection [ 10–12 ]. Among the current medical wound dressings (gauze, adhesive bandage, foam and hydrogel, etc.) [ 13–15 ], hydrogel is a good platform for antibiotic controlled release [ 16 ]. At the same time, hydrogel offers the advantages that other materials do not have, such as moisturizing, self-healing, and on-demand functional designs [ 17 , 18 ]. Therefore, it is of great practical significance to develop an antibacterial hydrogel-based antibiotic delivery system for MRSA-infected wounds.

After the formation of the wound, the locally recruited inflammatory cells immediately migrate to the wound site, making the wound repair enter the inflammatory phase [ 19 , 20 ]. However, excessive oxidative stress at the wound site can produce excessive ROS [ 21 ], which in turn triggers chronic inflammation [ 22 ], creating a vicious cycle. On the other hand, the colonization of MRSA in the wound bed undoubtedly leads to severe infection [ 23 ], exacerbating the inflammatory response and causing tissue damage [ 24 ]. Infection also weakens immune cells, making it difficult to reverse pathological changes, prolonging the inflammatory phase and hindering further wound repair [ 25 , 26 ]. Therefore, in order to treat infected wounds, it is necessary to remove bacteria [ 27 , 28 ], reduce ROS and inflammation [ 29–31 ], so as to restore balance in the microenvironment [ 32 , 33 ] of the wound site and facilitate orderly subsequent repair.

There have been studies on hydrogels for the treatment of MRSA infection from the perspective of antibacterial, anti-inflammatory and antioxidant, but the load of drugs is mostly reflected in the controlled release of a single drug. For example, due to the presence of carboxyl groups in pectin and gelatin, curcumin (Cur)-loaded photocrosslinked hydrogels composed of methacrylated gelatin and methacrylated pectin can release more Cur under alkaline conditions, showing great advantages for the treatment of infected wounds [ 34 ]. Singh et al. prepared a hydrogel system by chitosan and poly(N-isopropylacrylamide-co-methacrylic acid) (PNIPAM-co-MAA) microgels. Due to the temperature-responsiveness of PNIPAM and the pH-responsiveness of the carboxylic acid groups in MAA, the release of moxifloxacin in the hydrogel can achieve dual-responsive control of temperature and pH [ 35 ]. The above studies have shown that a single controlled release of a drug can only achieve a single purpose, which cannot meet the multiple needs of infected wounds for antibacterial and anti-inflammatory etc., and also cannot meet the spatiotemporally sequential delivery of multiple needs. Therefore, design of hydrogel dressings that can deliver different drugs at different times to treat MRSA-infected wounds is a promising strategy.

Moxifloxacin is a broad-spectrum fluoroquinolone antibiotic [ 36 ], which is an appropriate choice for the treatment of skin bacterial infections. Curcumin is a kind of diketone polyphenol compound, which has many functions such as antibacterial, anti-inflammatory, and antioxidant [ 37–39 ]. The safety of Cur has been certified by the World Health Organization and U.S. Food and Drug Administration [ 40 ]. Besides, the industrial production of Cur is relatively mature, and the product is cheap and economical [ 41 ]. Based on the hydrophilicity of moxifloxacin hydrochloride and the hydrophobicity of Cur, they can be designed to exist in two different forms in hydrogels, that is, moxifloxacin hydrochloride can be loaded in the hydrogel by directly mixed with the hydrogel precursor solution. And for Cur, it can be firstly mixed with Pluronic F127 (PF) to form Cur-encapsulated PF micelles (Cur-PF), and then loaded into the hydrogel to achieve sustained release of Cur [ 42 ]. So, the release of Cur is characterized by sustained release, while the release of moxifloxacin directly loaded in the hydrogel is characterized by high efficiency and fast release. This is consistent with the treatment characteristics of MRSA-infected wounds, and has not been reported.

In this study, ROS-responsive HPA hydrogel loaded with antibiotic moxifloxacin (M) and anti-inflammatory ingredient Cur-PF was prepared by cross-linking of phenylboronic acid ester between hyaluronic acid-grafted 3-amino phenylboronic acid (HA-PBA) and polyvinyl alcohol (PVA) to treat MRSA-infected wound healing. In this hydrogel, the phenylboronic acid ester bond formed by HA-PBA and PVA has ROS responsiveness, which can realize the responsive release of drugs. Moxifloxacin and Cur exist in different forms in the hydrogel, which makes them spatially different from each other. Besides, the spatial difference between the two drugs results in a difference in their release rate, which further results in a time difference. Therefore, the hydrogel designed above can the hydrogel prepared in this study showed rapidly release of moxifloxacin to endow antibacterial property, and exhibited sustained release of Cur for anti-inflammatory under ROS-responsive conditions. Those differences meet the different needs of MRSA-infected wounds at different treatment periods based on spatiotemporally sequential delivery time-space sequential release of the two drugs. The swelling, degradation, self-healing, biocompatibility, responsive sequential release, antibacterial, anti-inflammatory and antioxidant properties of the hydrogel were tested, and their effectiveness in repairing in full-thickness skin was verified in a MRSA-infected mouse skin wound model. This is the first time to realize the spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs on hyaluronic acid (HA)-based hydrogel for repairing the MRSA-infected skin wound of mouse.

Hyaluronic acid (Mn = 800 000 Da), 3-amino phenylboronic acid (PBA), polyvinyl alcohol type 224 (PVA), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC), N-hydroxysuccinimide (NHS), and 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazide (DPPH) were purchased from Macklin; Cur, PF, and 2′,7′-dichlorofluorescein diacetate (DCFH-DA) were purchased from Sigma Aldrich. All reagents were used directly without special purification.

Preparation of hyaluronic acid grafted 3-amino phenylboronic acid (HA-PBA)

HA (1 g, 2.5 mmol) was firstly dissolved in 100 ml of deionized water, then the EDC (575 mg, 3 mmol) and NHS (345 mg, 3 mmol) were added. The pH of the solution was controlled at 5 ∼ 6. After the above mixed solution was stirred for 20 min, PBA (410.65 mg, 3 mmol) was added to the mixture, and 1 M HCl was used to control the pH of the solution at 5 ∼ 6. The reaction lasted overnight at room temperature. Then, the mixture was dialyzed (3500 KD) for 3 days, and freeze-dried.

Preparation of curcumin encapsulated Pluronic F127 micelles (Cur-PF)

According to the references [ 43 ], a one-step solid dispersion method was used to synthesize Cur-PF micelle. The feed ratio of Cur and PF polymer was 2:98.

Preparation of hydrogels

The synthesized HA-PBA polymer was dissolved in distilled water at a concentration of 3 wt%; PVA was dissolved in distilled water at a concentration of 10 wt%. Then, the HA-PBA and PVA were mixed in a certain volume ratio and vortex rapidly to obtain HPA hydrogels with final HA-PBA concentration of 1.5 wt% and the final PVA concentration of 1, 2 and 3 wt%, and these hydrogels were named as HPA1, HPA2, and HPA3, respectively.

To prepare the hydrogels loaded with Cur and moxifloxacin, the Cur-PF was dissolved in distilled water at a concentration of 30 wt%. Then, Cur-PF and HA-PBA were mixed in advance with a certain volume ratio, and the final concentration of Cur-PF was 5 wt%. The mass content of moxifloxacin and Cur in Cur-PF was the same, and they were premixed into HA-PBA solution. Then, the above mixed solution was mixed with PVA solution, and the hydrogels obtained were named as HPA1/M&Cur-PF, HPA2/M&Cur-PF and HPA3/M&Cur-PF, respectively.

The characterization of hydrogels

The tests of nuclear magnetic resonance ( 1 H-NMR) [ 44 ], Fourier transform infrared spectroscopy (FT-IR) [ 45 ], field emission scanning electron microscopy (SEM) [ 46 ], transmission electron microscope (TEM) [ 43 ], swelling [ 47 ], degradation [ 48 ], self-healing, rheological and mechanical properties [ 49 ], DPPH scavenging [ 50 ], ROS scavenging [ 51 ] and biocompatibility were all carried out according to the literature [ 52 ]. And the operational details can be found in SI. All animal experiments were conducted in accordance with the current guidelines for experimental animal care, and were approved by the Professional Committee of Xi’an Jiaotong University.

In vitro drug release assay

The drug release characteristics of HPA/M&Cur-PF hydrogels were tested in PBS or 1 mM H 2 O 2 for moxifloxacin and Cur. The drug released from the hydrogel was analyzed by UV-Vis spectrophotometer at 420 nm (Cur) and 288.57 nm (Moxifloxacin), respectively [ 53 ]. The details can be found in SI.

Antibacterial property test of the hydrogels

To test the antibacterial properties of the released drugs from the HPA/M&Cur-PF hydrogels, the samples were placed on solid medium (nutrient agar) in contact with the bacteria and the zones of inhibition around each sample were measured to record the antibacterial effect of HPA/M hydrogel loaded with moxifloxacin, and HPA/M&Cur-PF hydrogel loaded with moxifloxacin and Cur [ 44 ]. The details can be found in SI.

Anti-inflammatory experiments of HPA hydrogels

Macrophage polarization was induced by lipopolysaccharide (LPS). Hydrogel leachate was used instead of culture medium, and after incubation for 48 h, total RNA of macrophages was isolated and reverse-transcribed and amplified for further analysis of related gene expression [ 54 ].

Wound healing in an in vivo MRSA infection model

To further evaluate the promoting effect of HPA/M&Cur-PF hydrogel on wound healing, a wound healing model of MRSA-infected mouse back skin was established. The details can be found in SI.

Histological and immunohistochemical evaluation

Collect wound specimens on the Days 3, 7, and 14 after treatment. Then, hematoxylin–eosin (HE) staining was performed to evaluate the epidermal regeneration and inflammation of the wound. Masson staining was used to evaluate collagen deposition in wound beds. On the other hand, immunofluorescence staining was performed using TNF-α and VEGF antibodies, respectively.

Statistical analysis

All experimental data were statistically analyzed, and the results were expressed as mean ± SD. Statistical differences were determined by one-way ANOVA and a Student t -test. In all cases, if P  <   0.05, there is a significant difference.

Ethics approval

All protocols about animal experiments were approved by the animal research committee of Xi’an Jiaotong University (approval number: 2023-1469).

Synthesis of hydrogel

In this study, based on the dynamic phenylboronic acid ester bond between HA-PBA and PVA, and Cur-PF and antibiotic moxifloxacin (M), a series of hydrogel dressings with good antibacterial, anti-inflammatory and antioxidant effects, and stimulus-responsive drug release in different spatiotemporal sequences were prepared. Figure 1 showed the overall strategy to prepare HPA/M&Cur-PF hydrogels for MRSA-infected skin wounds healing. Firstly, PBA was grafted onto HA through amidation reaction, forming HA-PBA ( Figure 1A ). Secondly, Cur was encapsulated in PF by taking advantage of the self-assembly characteristics of PF to form Cur-PF ( Figure 1B ). Figure 1C is the structural diagram of PVA. Figure 1D showed the specific preparation procedure of HPA/M&Cur-PF hydrogel, namely Cur-PF and moxifloxacin were first mixed with HA-PBA precursor solution, and then HA-PBA in the mixed solution formed phenylboronic acid ester dynamic bond through the combination of phenylboronic acid group with the diol group structure on PVA. The hydrogel was named as HA-PBA/PVA1 (HPA1), HA-PBA/PVA2 (HPA2), and HA-PBA/PVA3 (HPA3) according to the final concentration of PVA in the hydrogel varying from 10, 20–30 mg/ml. Figure 1E showed the application of HPA/M&Cur-PF hydrogel in the MRSA-infected skin wound of mice. Based on the response of phenylboronic acid ester dynamic bond to ROS, and the different loading forms of moxifloxacin and Cur in hydrogel, two drugs in the HPA/M&Cur-PF hydrogel achieved stimulus-responsive release in different spatiotemporal sequences. When the HPA/M&Cur-PF hydrogel was applied to the MRSA-infected skin wounds of mice, it can achieve responsive anti-inflammatory and antioxidant property on the basis of rapid antibacterial action, and synergistically promote the wound repair.

Schematic diagram of preparation and application of HPA/M&Cur-PF hydrogel. ( A ) Hyaluronic acid-grafted 3-amino phenylboronic acid (HA-PBA). ( B ) polyvinyl alcohol (PVA). ( C ) preparation of curcumin-encapsulated pluronic F127 micelles (Cur-PF). ( D ) structure diagram of HPA/M&Cur-PF hydrogel. ( E ) Application of hydrogel in MRSA-infected skin wound healing of mouse.

As shown in Figure 2A , the peak of HA-PBA at 7–8 ppm in the 1 H-NMR spectrum comes from hydrogen on the benzene ring, demonstrating the successful grafting of PBA. The chemical shifts ( δ , ppm) of the peaks were assigned as below: 7.58 (m, 4H, A), 1.89 (s, 3H, B). It could be seen that phenylboronic acid was successfully grafted. Through integral calculation, the grafting ratio of PBA was 14.2%. Meanwhile, as shown in Figure 2B , the changes in the peaks at 1459 and 1517 cm −1 in the FT-IR spectrum came from benzene ring, and the peak at 1340 cm −1 is attributed to the stretching vibration of the B–O, once again proving the successful grafting of PBA. The TEM image of Cur-PF in Figure 2C confirmed the formation of Cur-PF micelles with a diameter of around 300 nm, which is consistent with the results of previous studies [ 43 ]. As shown in the Supplementary Figure S1 , the diameter of Cur-PF micelles was tested by using dynamic light scattering, and the experimental results showed that it is distributed in the range of 220–458 nm, which is consistent with the TEM results. Figure 2D showed the state of HPA hydrogel before and after gelation. Both HA-PBA and PVA are in the liquid state with fluidity. After mixing and shaking them in a certain proportion within 2 min, the gelatinized HPA hydrogel without flowing state can be observed. The test tube inversion method was used to measure the gelation time at constant temperature of 25°C. Supplementary Table S1 showed the average gelation time of the HPA2 hydrogel was 50.4 ± 2.4 s, while the gelation time of the HPA2/PF hydrogel was a little longer, about 69.3 ± 2.1 s, which may be due to the surfactant of PF [ 55 , 56 ]. Figure 2E showed the SEM images of all hydrogels. With the increase of PVA concentration in HPA1, HPA2 and HPA3 hydrogel, the crosslinking-density of hydrogels was increased, and the pore size also became smaller. When the PF micelles were added, it can be seen that the pore size of HPA2/PF hydrogel was more uniform than that of HPA2, which may be caused by the nature of non-ionic surfactant of PF. Figure 2F showed the statistics of the pore diameter of all hydrogels, which more intuitively showed that with increasing of PVA concentration, the pore size of the hydrogel gradually decreased from 191.8 ± 49.3 µm of HPA1 hydrogel to 92.6 ± 30.7, 68.3 ± 24.4 and 66.2 ± 10.3 µm for HPA2, HPA3 and HPA2/PF hydrogels, respectively. And the pore size of HPA2/PF hydrogel was more uniform compared to HPA2 hydrogel.

( A ) 1 H-NMR spectrum of HA-PBA, A represents the hydrogen on the benzene ring and B represents the hydrogen on the methyl group. ( B ) FT-IR spectra of HA, PBA, and HA-PBA. ( C ) The TEM image of Cur-PF micelle. ( D ) Gelation display of HPA hydrogel. ( E ) HPA1, HPA2, HPA3 and of HPA2/PF hydrogels’ SEM image (scale bar: 200 μm) and ( F ) pore size diameter statistics.

Mechanical properties, swelling, degradation and self-healing of hydrogels

With the introduction of the wet healing theory [ 57 ], maintaining a certain level of humidity at the wound site is beneficial for the repair of skin wounds [ 58 ]. Figure 3A showed the equilibrium swelling ratio of HPA hydrogels, all hydrogels can absorb more than 60 times water of their own mass. The swelling ratio of HPA hydrogels decreased with increasing of PVA concentration, and their swelling ratios were 8878.8 ± 470.1%, 7360.0 ± 372.5% and 5971.1 ± 322.1% for HPA1, HPA2 and HPA3, respectively. This should be due to the increase of PVA content, which provides more crosslinkable sites and increases the crosslinking density within a certain range. Besides, the swelling ratio of HPA2/PF was 6560.5 ± 107.3%, slightly lower than that of HPA2 hydrogel, because of hydrogen bonding between PF micelles and HPA hydrogel network. The good swelling properties of the HPA hydrogels make it natural and great advantages in the management of wound exudate, and it can absorb the exudate well while maintaining the wound moist.

( A ) Swelling behavior of HPA hydrogels. ( B ) Degradation behavior of HPA hydrogels. ( C ) Rheological behavior of HPA hydrogels. ( D ) The strain–stress curves of HPA hydrogels during the compression test. ( E ) Self-healing display of HPA hydrogels. ( F ) The rheological properties of HPA2/PF hydrogel when alternate step strain switched from 1% to 1500%. ( G ) ROS-responsive properties of hydrogels. The release of ( H ) moxifloxacin and ( I ) curcumin from HPA2/M&Cur-PF hydrogels in PBS or H 2 O 2 .

Biodegradability is a crucial criterion for measuring medical materials [ 59 ]. Therefore, the degradation performance of HPA hydrogels was further evaluated. Figure 3B showed that all hydrogels have good degradability. With increasing of PVA concentration, the crosslinked network of hydrogels was closer, so the degradation rate of HPA3 hydrogels was the slowest. Specifically, after 3 days of testing, the remaining weight of HPA1, HPA2 and HPA3 hydrogels groups remained 54.6 ± 1.8%, 72.0 ± 4.0%, and 83.0 ± 1.7%, respectively. Since the addition of PF micelles maked the crosslinked network of hydrogel more closely, HPA2/PF degraded more slowly than HPA2, showed 88.0 ± 1.7% remaining weight after 3 days of testing. Importantly, the remaining weight of all hydrogels was less than 30% after the 12 days test. Experiments verified that all hydrogel dressings prepared in this study had reasonable degradation properties.

Appropriate modulus is very important for hydrogel dressings. It can provide a good mechanical matching between hydrogel dressings and skin tissues, ensure a comfortable sense of wear during use, and reduce physical damage to damaged tissues. Therefore, rheological tests were used to evaluate the properties of HPA hydrogels and Figure 3C showed that with increasing of PVA concentration, the modulus of the hydrogel showed a trend of gradual increase. The storage modulus of HPA1 was 40.6 Pa, that of HPA2 was 139.1 Pa, and that of HPA3 was 424.7 Pa. Due to the addition of PF micelles, the modulus of HPA2/PF hydrogel was also increased to 227.4 Pa compared with HPA2 hydrogel. The thermal stability of the hydrogels in the range of 25–40°C was tested. As shown in the Supplementary Figure S2 , the modulus of HPA2 and HPA2/PF hydrogels did not change much. In addition, we can clearly observe that the HPA2/PF hydrogel can still maintain the gel-forming state under the high temperature condition of 40°C. The hydrogel has good thermal stability between 25°C and 40°C, so when applied to the skin surface, the hydrogel can still maintain its own stability even under body temperature conditions.

Skin’s inevitable stretching during human activities is very easy to damage the hydrogel dressings. Therefore, higher requirements are put forward to the mechanical properties of hydrogels. As shown in Figure 3D , it can be seen from the stress–strain test that all hydrogels showed good compressibility. When the strain was 80%, with the increase of PVA concentration, the stress of the hydrogels was 2161.7, 2445.9 and 3547.0 Pa, respectively, and all hydrogels were unbroken. After the addition of PF micelles, the stress of HPA2/PF hydrogel increased to 4998.7 Pa at the strain of 80%. The above experimental results showed that the mechanical properties of the hydrogel gradually increase with increasing of PVA concentration, and it can be effectively improved by adding PF micelles. The results of the above tests showed that the properties of HPA hydrogels, including pore size, swelling, degradation, modulus, and mechanical properties, can be easily regulated by adjusting the ratio between components. This tunable property provides a broader selectivity for the hydrogel to adapt to different wound states and repair stages.

The damage of hydrogel dressing will lose the protective effect to wound, which puts forward requirements for the self-healing performance of skin wound dressing. As shown in Figure 3E , after the hydrogel was cut into two halves, it can quickly self-heal and merge within 5 min. Figure 3F showed that when the strain was higher than 1500%, G″ of hydrogel was higher than G′, which means that the hydrogel network was damaged. Therefore, by constantly switching low strain (γ = 1%) and high strain (γ = 1500%), the quantitative self-healing function was tested. At the beginning of the test, at the first low strain (γ = 1%), G′ and G″ was 241.3 and 138.4 Pa, respectively, and G′ > G″. After switching to the high strain (γ = 1500%), G′ changed to 27.6 Pa and G″ changed to 44.7 Pa, G″ > G′, which means that the hydrogel network crashed. In the following tests, when γ was cyclically transformed, G′ and G″ can recover to the initial value, with no significant difference in modulus compared to the first test. In conclusion, due to the existence of phenylboronic acid ester dynamic bond, the HPA hydrogel prepared in this study has good self-healing performance, which provides the quickly restore of structural integrity when it is ruptured under external force, not only ensures the physical barrier effect, but also avoids the possible bacterial invasion after rupture. As shown in the Supplementary Figure S3 , shear rate scanning measurements indicate that all hydrogels in this experiment exhibit shear-thinning behavior, where the viscosity of the material depends on the shear force, and thus the hydrogels in this work are injectable.

ROS-responsive drug release of hydrogels

The biggest problem of using antibiotics is bacterial resistance [ 60 ]. Loading drugs in hydrogels can greatly avoid the repeated use of drugs and reduce the generation of bacterial resistance. In particular, the ROS response caused by the presence of phenylboronic acid dynamic ester bond in HPA hydrogel can realize intelligent on-demand drug delivery in the hydrogel system [ 61 ]. As shown in Figure 3G , when 200 μl of 10 mM H 2 O 2 was added to the prepared 500 μl HPA2/M&Cur-PF hydrogel, a certain fluidity of the hydrogel can be observed just within 20 min, and the hydrogel network collapsed completely at 4 h. This is mainly due to the destruction of the hydrogel network structure caused by the reaction of the phenylboronic acid ester structure with H 2 O 2 . As shown in Supplementary Figure S4 , the modulus of HPA2 hydrogels and HPA2/PF hydrogels were tested under 1 mM H 2 O 2 or PBS for the same time, respectively. At 10 min, the modulus of the hydrogel in PBS did not change much compared to the initial value, but the modulus of the hydrogel in H 2 O 2 decreased dramatically by about 200 Pa. At 20 min, the modulus of the hydrogel in PBS decreased due to the swelling and absorbing of water, and at this time, the hydrogel in H 2 O 2 was close to the state of non-gelation. In this study, two drugs were loaded into the hydrogel dressings. One was moxifloxacin with antibacterial effect directly mixed in the hydrogel, and the other was Cur with anti-inflammatory and antioxidant functions encapsulated in PF micelles. As shown in Figure 3H , the release rate of moxifloxacin in PBS is relatively slow, and the release time can be more than 250 h. While in 1 mM H 2 O 2 release solution, the release amount of moxifloxacin in 36 h can reach more than 80%. The above results showed that hydrogel can deliver antibiotics quickly and effectively after being applied to wounds due to the ROS responsiveness of phenylboronic acid ester bonds. These results mean that when bacterial infection is serious, leading to excessive inflammation and the production of a large amount of ROS, the ROS response can be quickly activated, so that the antibiotic can be released rapidly to prevent the continuation of severe infection in a short time. The release amount of Cur in PBS and H 2 0 2 was 14% and 38% at 24 h. In summary, moxifloxacin can be rapidly released more than 80% within 36 h, and Cur can be continuously released within 288 h under the action of 1 mM H 2 O 2 . In a word, the spatiotemporally sequential release of these two drugs allows for a rapid antimicrobial treatment and then sustained anti-inflammatory and antioxidant effect at the site of the infected wound.

Antibacterial properties of hydrogels

The antibacterial effect of the antibiotics released from the hydrogel was verified by the inhibition zone test. The control group is just the holes punched on the agar plate by the punch, so the diameter size and shape of the control group do not change with time and environmental factors, and at the same time to ensure that the initial diameter is the same between every group, and to confirm whether the experimental group formed a ring of inhibition around the holes. As shown in Figure 4A , at the 12 h, the diameter of the inhibition zone for HPA2/M hydrogel and HPA2/M&Cur-PF hydrogel against E. coli were 2.20 ± 0.02 and 2.26 ± 0.02 cm, respectively, and the diameter of the inhibition zone against MRSA were 2.08 ± 0.01 and 2.05 ± 0.01 cm, respectively. This suggested that the antibacterial effect of HPA2/M&Cur-PF hydrogels is better than that of HPA2/M hydrogels. Until the 60 h, there was still obvious inhibition zone. At this time, the diameter of HPA2/M hydrogel and HPA2/M&Cur-PF hydrogel against E. coli was 1.30 ± 0.09 and 1.50 ± 0.02 cm, respectively, and the diameter of the inhibition zone against MRSA was 1.24 ± 0.02 and 1.33 ± 0.01 cm, respectively. The appearance of inhibition zone indicates that moxifloxacin and Cur-PF loaded in the hydrogel diffuse to the surrounding environment, thus killing the bacteria in a certain area. In addition, the inhibition zone diameter of HPA2/M&Cur-PF hydrogel for MRSA was statistically larger than HPA2/M hydrogel, and showed significant different ( P  < 0.05). This is because Cur also has antibacterial effect [ 62 ], which is synergistic with moxifloxacin. More obviously, at the 84 h, the inhibition zone of HPA2/M hydrogel had disappeared, while the inhibition zone of HPA2/M&Cur-PF hydrogel was still slightly larger than 7 mm, suggesting that HPA2/M&Cur-PF hydrogels had better antibacterial effect than HPA2/M hydrogels. In conclusion, the hydrogel dressings prepared in this study had good sustained antibacterial effect.

( A ) The inhibition zone of hydrogel for E. coli and MRSA within 96 h. In the figure, 1, 2 and 3 represent the control group, the HPA2/M group and the HPA2/M&Cur-PF group, respectively. Statistics of inhibition zone of hydrogel for ( B ) E. coli and ( C ) MRSA within 96 h (* P  < 0.05).

Biocompatibility of hydrogel

Good biocompatibility is an essential prerequisite for biomedical materials [ 63 ]. In this study, the prepared hydrogels were tested from the aspects of blood compatibility and cell compatibility. As shown in Figure 5A , in the blood compatibility test, the materials in experimental group showed comparable to or even lower hemolysis ratio than that of the PBS group, with hemolysis ratio of below 5%, which was considered to be a good range of blood compatibility. The test results indicated that they will not cause significant hemolysis when applied to biological tissues. Figure 5B showed the cell compatibility of the hydrogels. Because of the good adhesion and proliferation effect of HA on cells [ 64 ], the cell viability of HPA2 hydrogel group was higher than that of the control group after co-culture. The cell viability of the HPA2/M&Cur-PF group compared to the control group was 80.3%, 82.1%, and 94.4% in the first 3 days, respectively. Although the cell viability of the experimental group was slightly decreased in the first 2 days of testing compared to the control group, the significant differences were all P  < 0.05, indicating that the material was not toxic. Figure 5C exhibited the Live/Dead staining images of L929 cells after co-cultured with the hydrogel leachate for one day, which is consistent with the quantitative statistical results of cell viability. In general, the hydrogel dressings prepared in this study had good biocompatibility.

( A ) Hemolysis ratio of hydrogel. ( B ) Cell compatibility of hydrogel on L929 cells within 3 days test. ( C ) Live/dead straining of L929 cells on the first day. ( D ) DPPH scavenging statistics of hydrogel. ( E ) Representative images of ROS scavenging experiments and ( F ) statistical results for fluorescent areas. Statistic of expression results of ( G ) TNF-α and ( H ) IL-1β after application of hydrogels on macrophages (* P  < 0.05, ** P  < 0.01, *** P  < 0.001).

Antioxidation and anti-inflammation of hydrogel

If MRSA-infected wounds are not treated in a timely and appropriate manner, it can easily change to severe infection, causing severe inflammation at the wound site, and producing a large amount of ROS through oxidative stress [ 65 , 66 ]. Therefore, we first used the scavenging experiment of stable free radical DPPH• to evaluate the antioxidant properties of the hydrogels. Figure 5D showed that the presence of PBA group brings little DPPH• scavenging capacity to the hydrogels. Furthermore, due to the good antioxidant capacity of Cur, 500 μl of HPA2/Cur-PF hydrogel can scavenge more than 90% of DPPH. In addition, Figure 5E further showed the ROS scavenging ability of the hydrogels by DCFH-DA staining. LPS-induced macrophage (RAW 264.7) produced a large amount of ROS, while normal macrophage (RAW 264.7) cells in the control group only produced a small amount of ROS and the HPA2/Cur-PF hydrogel group showed similar or even lower ROS intensity than the control group. The statistical results in Figure 5F showed that the ROS production in the experimental group was not significantly different from that in the control group. As is well known, high concentrations of ROS can cause DNA damage and cell death, while low concentrations of ROS play a crucial role in signal transduction and wound repair [ 67 ]. Therefore, the experimental group didn’t show a significant different amount of ROS compared to the control group, which is very beneficial for wound repair. As shown in Figure 5G and H , the significantly increased expression levels of TNF-α and IL-1β in the LPS group indicate that macrophage (RAW 264.7) cells were successfully induced into an inflammatory state, while the expression levels of both inflammatory factors were significantly reduced under the action of the hydrogel group, indicating that the hydrogel has significant anti-inflammatory effects. In summary, the HPA2/Cur-PF hydrogels have suitable antioxidant and anti-inflammatory effects, which lays a strong foundation for its use as a dressing for wound with MRSA infection.

Promoting effect of HPA/M&Cur-PF hydrogel on healing of MRSA-infected skin wounds

A series of in vitro experiments have verified the good antibacterial, anti-inflammatory and antioxidant effects of HPA/M&Cur-PF hydrogel. We further established a MRSA-infected mouse back skin wound model, and evaluated the repair-promoting effect of the hydrogel prepared in this study. Figure 6A showed the entire time course from modeling to wound repair. First, a circular wound with a diameter of 8 mm was created on the back skin of mouse, and 10 μl of 10 8 CFU/ml MRSA were injected. On the 3rd, 7th, and 14th day, the skin at the wound site was observed and sectioned for study. The commercially available Tegaderm™ dressing was selected as the control group [ 68 ]. Based on the previous characterization tests, HPA2 hydrogel was selected as the representative and applied in the subsequent animal experiments. The experimental groups were HPA2 hydrogel, HPA2/M hydrogel loaded with moxifloxacin (the concentration of moxifloxacin was 2 mg/ml), HPA2/Cur-PF hydrogel loaded with Cur-encapsulated PF (the concentration of Cur was 2 mg/ml), and HPA2/M&Cur-PF hydrogel loaded with moxifloxacin and Cur-encapsulated PF (the concentration of moxifloxacin and Cur were both 2 mg/ml). In Figure 6B , the wounds in each group showed different phenomena over time after surgery. Control group showed significant suppuration on the third day after treatment, which even lasted until the seventh day. This is consistent with the clinical phenomenon that MRSA-infected wounds have severe bacterial infection with a lot of inflammation and even difficulty in healing. The HPA2 hydrogel group did not have a good anti-infection effect compared to the other three experimental groups, and no significant sepsis was found. In Figure 6C , the wound areas of each group were plotted over time. In Figure 6D , the wound closure ratio of each group was analyzed. Compared with the control group, after 7 days of treatment, there was a significant difference ( P  < 0.01) in the wound closure of HPA2, HPA2/M, HPA2/Cur-PF, and HPA2/M&Cur-PF group, respectively. Besides, there was a significant difference in the wound closure of HPA2/M&Cur-PF and HPA2 ( P  < 0.05), which indicated that the hydrogel loaded with the two drugs promoted better wound repair. On the 14th day, there still was a significant difference ( P  < 0.01) between HPA2/M&Cur-PF and HPA2/M and HPA2/Cur-PF, which proved that moxifloxacin and Cur promoted MRSA-infected wound healing, and the synergistic effect of the two drugs was more favorable for wound repair. In conclusion, on the 14th day, all hydrogel groups showed good healing effect. The HPA2/M&Cur-PF hydrogel group showed the best healing effect, with almost complete wound closure. But the control group still had an obvious wound, with 34.3% of the remaining wound area, which was significantly different from the other hydrogel groups ( P  < 0.001).

( A ) Schematic diagram of the in vivo wound healing experimental program in an infected full-thickness skin defect model. ( B ) The pictures of wounds on the 3rd, 7th, and 14th day were divided into five groups: Tegaderm™ film dressing (control), HPA2 hydrogel, HPA2/M hydrogel, HPA2/Cur-PF hydrogel and HPA2/M&Cur-PF hydrogel, and ( C ) plotting of wound area over time. ( D ) Statistics on changes in wound closure ratio. ( E ) HE staining of the wound site on the 3rd, 7th, and 14th day. ( F ) Masson staining of the wound site on the seventh day. ( G ) Statistics of relative inflammation at the wound site on the third day. ( H ) Thickness of regenerated epidermis at the wound site on the seventh day. ( I ) Statistics of relative collagen deposition at the wound site on the seventh day (* P  < 0.05, ** P  < 0.01, *** P  < 0.001).

The effect of each group on wound repair was further evaluated by HE staining. In Figure 6E , on the third day, a large amount of inflammation can be seen in the control group, while the inflammation in other hydrogel groups is relatively low. Figure 6G showed the statistics of inflammation. Due to the effects of moxifloxacin and Cur, the inflammation of HPA2/M, HPA2/Cur-PF and HPA2/M&Cur-PF hydrogel groups is significantly lower than that of the control group and HPA2 hydrogel group ( P  < 0.01). The dual effect of antibacterial and anti-inflammatory effects makes the relative amount of inflammation between HPA2/M&Cur-PF hydrogel group and HPA2/M and HPA2/Cur-PF have a significant difference ( P  < 0.01). In Figure 6E , on the seventh day, the epidermal regeneration in the control group was discontinuous, accompanied by blood scabs, which was mainly because the wound site was infected by MRSA and the bacteria were not removed in time, and the infection also made it difficult for wound healing to continue the next step. However, obvious continuous epidermal regeneration was seen in HPA2/M, HPA2/Cur-PF and HPA2/M&Cur-PF hydrogel groups. In Figure 6H , statistics showed that the thickness of regenerated epidermis in HPA2/M&Cur-PF hydrogel group was the thickest, which was significantly different from the other four groups ( P  < 0.01). The metabolism of collagen participates in the whole process of wound repair and the regenerated collagen constitutes an important part of the repaired wound, so its importance is obvious. In Figure 6F , masson staining showed the deposition of collagen in each group on the seventh day. And in Figure 6I , a statistical analysis of the masson staining was performed. The relative collagen deposition of the four test groups was significantly higher than that of the control group, and the difference was significant compared with the control group ( P  < 0.05). Among the experimental groups, the HPA2/M&Cur-PF group, which was more effective for wound repair, had 3.4 times more collagen deposition than the control group. In summary, HPA2/M&Cur-PF hydrogel dressings can promote wound closure, reduce inflammation and promote collagen deposition in MRSA-infected mouse skin wound healing.

Immunofluorescence staining analysis

Wound healing is a complex process, and the expression of relevant cytokines can reflect some specific situations during the wound healing process [ 69 , 70 ]. The third day after wound formation is considered to be the inflammatory period. At this time, a proinflammatory cytokine, tumor necrosis factor (TNF-α) [ 71 ], was selected to evaluate the effect of hydrogel on inflammation control. From the immunofluorescence staining analysis of TNF-α in Figure 7A and the statistics in Figure 7B , it can be seen that the colonization of bacteria at the wound leads to the aggravation of inflammation, and there were significant differences between control and HPA2/M, HPA2/Cur-PF and HPA2/M&Cur-PF hydrogel groups, respectively. Specifically, inflammation in HPA2/M and HPA2/Cur-PF hydrogel groups was significantly reduced. The reduction in inflammation in the HPA2/M hydrogel was due to the antibacterial effect of moxifloxacin, while the reduction in inflammation in HPA2/Cur-PF hydrogel was due to the antibacterial and anti-inflammatory effects of Cur. Most importantly, HPA2/M&Cur-PF hydrogel group has the synergistic effect of two drugs, so it showed the lowest inflammation. The generation of blood vessels is an essential physiological process in wound healing, which can rebuild normal blood flow for wound tissue, provide nutrition and oxygen for the tissue, and accelerate the process of wound repair [ 72 , 73 ]. On the seventh day, vascular endothelial growth factor (VEGF) [ 74 ] was used to evaluate the neovascularization at the wound. Figure 7A showed the immunofluorescence staining analysis of VEGF and Figure 7C showed the statistical results. Significant differences ( P  < 0.01) were found between the control group and the HPA2/M hydrogel group, the HPA2/Cur-PF hydrogel group and the HPA2/M&Cur-PF hydrogel group, respectively. In HPA2/M and HPA2/Cur-PF hydrogel groups, due to the effect of two drugs to avoid bacterial infection and inflammation in the early stage, the hydrogel promoted the formation of new blood vessels. In conclusion, based on the expression of TNF-α and VEGF, HPA2/M&Cur-PF hydrogel showed better therapeutic effect in MRSA-infected skin wounds.

( A ) Immunofluorescence staining images of TNF-α on the third day and VEGF on the seventh day, with green indicating TNF-α expression and red indicating VEGF. ( B ) Quantitative analysis of the relative area percentage ( n  = 3) of TNF-α and ( C ) VEGF. For all quantitative analyses, the commercial film group data for TNF-α on the third day and VEGF on the seventh day were set as 100% (* P  < 0.05, ** P  < 0.01).

In this study, HA-based HPA/M&Cur-PF hydrogel dressing with spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs was constructed based on the dynamic bond of phenylboronic acid ester for the first time, and was used to repair MRSA-infected skin wounds. The rheological properties, self-healing, biocompatibility, responsiveness, spatiotemporally sequential drug delivery, antibacterial, antioxidant and anti-inflammatory properties of hydrogels were verified. Under ROS conditions, hydrogels can release more than 80% of moxifloxacin within 36 h to perform quickly anti-infection effect, and release Cur up to 288 h to perform a sustained anti-inflammation effect. Finally, in the MRSA-infected mouse skin wound healing, the hydrogel-treated group exhibited faster wound closure, reduced inflammation, and promoted epidermal growth and collagen deposition. Immunofluorescence staining results also demonstrated the hydrogels’ ability to reduce inflammation while also promoting angiogenesis. In conclusion, HPA/M&Cur-PF hydrogel dressing has a significant effect on the repair of skin wounds infected by MRSA, providing ideas for responsive spatiotemporally sequential drug delivery strategies.

Supplementary data are available at Regenerative Biomaterials online.

This work was jointly supported by the National Natural Science Foundation of China (grant numbers 51973172, 52273149), supported by 111 Project 2.0 (grant number BPO618008), the Natural Science Foundation of Shaanxi Province (grant number 2020JC-03), and China Postdoctoral Science Foundation (grant number 2022M712498), State Key Laboratory for Mechanical Behavior of Materials, and the World-Class Universities (Disciplines) and the Characteristic Development Guidance Funds for the Central Universities.

Conflicts of interest statement . None declared.

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• anti-inflammatory agents
• inflammation
• moxifloxacin
• anti-bacterial agents
• methicillin-resistant staphylococcus aureus

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