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. Author manuscript; available in PMC: 2024 Nov 1.
Published in final edited form as: J Tissue Viability. 2023 Aug 28;32(4):527–535. doi: 10.1016/j.jtv.2023.08.004

Development and use of a porcine model with clinically relevant chronic infected wounds

Josie Shiff a, Katie Schwartz a, Bryan Hausman a, Dhruv R Seshadri a,b, Kath M Bogie a,b,*
PMCID: PMC11419285  NIHMSID: NIHMS2021991  PMID: 37716845

Abstract

Chronic ischemic wounds affect millions of people causing significant pain and disability. They can be considered to be stalled in the inflammatory stage and cannot heal without additional measures. A valid animal model is necessary to evaluate the efficacy of topical wound healing therapies and wearable technologies. A porcine model, although higher in cost, maintenance, and space requirements, is superior to the commonly used rodent or rabbit model for wound healing. Previous studies have shown that pig wounds have greater similarity to human wounds in responses to a variety of treatments, including wound dressings and antibiotics. The current study created a porcine model of large chronic wounds to assess a wearable electroceutical technology, with monitoring of healing variables and infection. Electroceutical therapy is the only adjunctive treatment recommended for chronic wound therapy. A porcine model of large chronic wounds of clinically realistic size was created and utilized to evaluate a wearable electroceutical biotechnology. Multivariate non-invasive assessment was used to monitor wound progression over multiple timepoints. Outcomes suggest that a wearable electrostimulation bandage, has the potential to offer therapeutic benefit in human wounds. The tested wearable device provides the same proven effectiveness of traditional electroceutical therapy while mitigating commonly cited barriers, including substantial time requirements, and availability and complexity of currently available equipment, preventing its implementation in routine wound care. The model is also appropriate for evaluation of other wearables or topical therapeutics.

Keywords: Ischemic wounds, Electroceutical therapy, Porcine model, Wearable technology

1. Introduction

Chronic ischemic wounds affect more than 6 million people in the United States, causing significant pain and disability [1]. These wounds fail to proceed along the normal healing pathway and are a major clinical challenge for many people with physical impairment and/or disability. Traditional methods to promote healing have limited efficacy, leading to long-term impaired quality of life, increased risk of mortality, and significant medical costs for continuous treatment. Persons with chronic disease and disabilities face increasing risk as they age. [2,3,4] The management of chronic wounds places a significant and increasing load on healthcare systems due to repeated out-patient clinic visits and/or re-hospitalization. Nearly a decade ago, the US healthcare cost burden was estimated at $6 to $15 billion per year [5], and is increasing steadily due to the growing prevalence of chronic wounds. The demand for wound care is expected to expand at a compound annual growth rate of 4.1% from 2023 to 2030 in the US and globally at 5% during the same period [6]. Recently, Carter et al. reported that wound prevalence increased between 2014 and 2019, with a cost in the US of $22.5–67.0 billion for 2019 [7].

Chronic wounds can be considered to be stalled in the inflammatory stage and thus cannot heal without additional measures [8]. The presence of multiple species of bacteria, the most common being Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, also inhibit healing Once they occur, these infections often last for months and explain the majority of mortality from chronic wounds [9]. Prolonged inflammation has been implicated in the high rate of bacterial colonization for these wounds, although a causative relationship has not yet been defined [10]. Antibiotics are showing reduced efficacy in the face of multidrug-resistant bacteria [11] and do not address biofilm formation or control [12]. These bacteria are present both as planktonic bacterial colonization and organized into biofilms, large collections of bacteria that protect them from being killed by antibiotics or the immune system [1]. Costerton et al. originally proposed that 65% of chronic infections are actually due to biofilm which may severely inhibit healing [13]. Wolcott et al. and others have proposed that it is these biofilms that cause the chronicity, perpetual inflammation, and increased antimicrobial tolerance associated with non-healing wounds [14,15]. The presence of biofilm has been shown to directly cause delayed reepithelialization in a mouse skin wound model [16]. In order to achieve effective healing, it is thus necessary to target not just the individual species of bacteria present, but also the resident biofilm.

A valid animal model is necessary to evaluate the efficacy of topical wound healing therapies and wearable technologies. A porcine model, although higher in cost, maintenance, and space requirements, is superior to the commonly used rodent or rabbit model for wound healing [17]. Pigs have the greatest similarity to humans in overall anatomy, physiological processes, and skin—dermis and epidermis thickness, hair covering, collagen structure, blood vessel distribution, protein composition, and adipose content [18–20]. Pig wounds heal by the same reepithelialization pathway as human wounds; in contrast, rodent and rabbit wounds heal by wound contraction.

Previous studies have shown that pig wounds are similar to human wounds in responses to a variety of treatments, including wound dressings and antibiotics. Overall, Sullivan et al. found a 78% concordance between porcine and human responses to wound therapies, as opposed to 53% in small mammals, confirming that the physiological similarities between pigs and humans make the porcine model optimal for wound healing based on previously tested treatments [18].

The current study created a porcine model of large chronic wounds to assess a wearable adjunctive therapeutic technology, with monitoring of healing variables and infection. The model has been developed to address the need for animals models with wounds of a clinically relevant size appropriate for evaluation of other wearables or topical therapeutics, which has been recognized as a need in the field [17]. In this development study, a wireless electroceutical bandage was compared to standard of care (SoC) treatment in wounds of a clinically relevant size.

2. Methods

All procedures and experimental protocols were approved by the Louis Stokes Cleveland VA Medical Center and Case Western Reserve Institutional Animal Care and Use Committees.

2.1. Bacterial strains

Pseudomonas aeruginosa RP1951 (PAO1F - wild type) and RP2229 (PAO1F with a chromosomally-integrated mCherry cassette), both gifts from Riesch lab.

2.2. Acclimation and preparation for initial procedure

Female American Yorkshire pigs, weighing 30–35 kg upon arrival, were used. Upon arrival, all pigs were administered a 5 mg/kg intramuscular dose of Ceftiofur to treat any existing bacterial infections. Animals were acclimated and monitored for health issues for at least 10 days prior to surgery. Standard veterinary care was provided for any identified issues. During the initial acclimation period, two pigs were cohoused. Following surgery they were housed singly in adjacent cages. Throughout the study, all pigs were fed a standard laboratory diet and received water ad libitum. Animals were continuously monitored for health issues and treated as needed under the direction of a licensed veterinarian. 24 h prior to the wound creation surgery, the pigs’ nape was shaved, cleaned, and a patch administering 2–4 μg/kg/hr of Fentanyl was affixed to provide prophylactic pain relief.

2.3. General Anesthesia Procedure

At least 18 h prior to the surgery the animals were fasted in preparation for anesthesia. For the surgical procedure, the animals were tranquilized using a 5–6 mg/kg dose of Telazol via intramuscular injection and then transferred to an operating suite. In the operating suite, the pig was intubated and anesthesia was maintained with 2–5% Isoflurane, as well as oxygen, throughout the course of the procedure. A peripheral intravenous (PIV) line was placed in the medial or lateral auricular vein to administer fluids or medication as needed. Vital signs were continuously monitored to ensure they remained within normal limits.

The pig’s dorsum was shaved and sterilely prepared with a 4% chlorhexidine surgical scrub. All instruments used for surgery and wound manipulation were sterilized prior to the procedure, and surgeons prepared using standard surgical sterility techniques.

Six full-thickness excisional wounds were created on the pig’s back, three on either side of the midline, with a template used to ensure bilateral consistency (Fig. 1a). Each wound was located 40 mm from the spinal vertebrae and separated from other wounds by a 60 mm margin. Prior to incision, the perimeter of each.

Fig. 1.

Fig. 1.

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Creation of pig model with large chronic wounds.

The layout of the wounds is shown in (a). Full thickness wounds were created on either side of the midline. The wound spacing was used for both sides to create space for 6 wounds each 60 mm in diameter (c, left), spaced 60 mm apart and 40 mm from the spine. The silicon wound block shown in (b) has flanges measuring 80 mm diameter.5 mm in height and the center measuring 40 mm in diameter and 10 mm in height. Wound blocks were placed in the wound bed, sutured in place and left in situ for 14 days.as shown in (c, right). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

wound site was injected with Lidocaine. A full thickness incision 2–3 mm in depth was made to create a wound 60 mm in diameter (Fig. 1c, left). All skin and fascia within the perimeter were removed. The wound margins were then undercut by 1 cm and sterile flanged silicon wound blocks (Fig. 1b) placed with the flanges in the undercut. The blocks were secured with a running locking suture (Fig. 1c, right). Following placement of all wound blocks, the pig was injected with 2 mg/kg dose of Carprofen via intramuscular injection for pain relief prior to reducing isoflurane anesthesia and initiating recovery.

2.4. Postoperative car

At the conclusion of the procedure, each wound was covered with a Telfa (Covidien, Minneapolis, MN) dressing and secured with Tegaderm (3M, Minneapolis, MN). The animal’s abdomen, from shoulder to hindleg, was wrapped with VetWrap elastic bandage (Prairie Horse Supply, Greenville, SC), covered with a flexible plastic mesh shield, and placed in a protective body jacket (Goat Tube®, Sullivan Supplies, Houston, TX). The animal was woken from anesthesia, given a 0.03 mg/kg dose of Buprenorphine via PIV, and placed in a single-occupancy pen.

2.5. Wound block care, removal, and placement of device

Wound blocks were left in situ for 14 days and bandages changed as necessary. Postoperative analgesia with Fentanyl and Carprofen was continued as clinically indicated. At least 14 days after initial surgery, the pig was prepared for initiation of wound infection. The pig was sedated prior to removal of the protective wrapping and wound blocks were removed. Each wound was inoculated with 3 × 107 CFU of mid-Log P. aeruginosa (both strains yielded similar results, data not shown) in PBS with 5 mM MgCl2 and 0.5 mM CaCl2. Pseudomonas aeruginosa was selected as the inoculant because it is both because it is both ubiquitous and commonly found in chronic wounds [21,22]. Within the three wounds placed on either side of the midline, one wound was randomly chosen to receive treatment, one to receive an inactive device, and one to receive the SoC, which consisted of a piece of Telfa covered with Tegaderm.

2.6. Investigational device

A wearable untethered electroceutical technology was employed in the current model [23]. The technology combines a disposable flexible and occlusive bandage with clear, absorbent window to view the wound bed without changing the dressing, together with a robust and reusable stimulation/control module and control software.

2.7. Wound monitoring

While exposed, each wound was monitored using multiple non-invasive procedures along with wound biopsy. Standard wound images were obtained using a 35 mm camera. The LifeViz 3D camera (QuantifiCare, Biot, France) was used to obtain 3D stereophotogrammetric images. An infra-red (IR) camera (Teledyne FLIR, Wilsonville, OR) was used to obtain wound region temperatures, including the periwound area as a baseline reference. MolecuLight (MolecuLight Inc., Toronto, Canada) images were also obtained, to determine the presence and location of biofilm. An ambient light image with distance markers was first taken, followed by a fluorescent light image, in accordance with manufacturer’s guidelines.

2.8. Wound pH

Measurements of pH were obtained from all wounds at every monitoring day. Surface pH was measured in the wound bed using a portable skin pH meter (Hanna Instruments, Ann Arbor, MI).

2.9. Wound swabs

were obtained using a planktonic swab of the entire wound. Wound biopsies were collected using 4 mm biopsy punches (VWR, Radnor, PA) from the center and margin of each wound. Biopsy sites were rotated at each timepoint to avoid taking a biopsy from a previous sampled location. Biopsies were immediately stored on dry ice and placed in −80 °C degree storage within 1–2 h of sample collection (MIQE1).

2.10. Continued monitoring

Following inoculation, monitoring procedures were conducted until the wounds healed with evaluations at 1, 3, 7, 10, 14, 17, 21, 28, and 35 days. The pigs were regularly inspected for any occurrence of strike-through in the wound dressings. When necessary, the dressings were removed between scheduled monitoring and the wounds immediately re-dressed to minimize any interruption in treatment. The pig was then re-bandaged as described in postoperative care. Anesthesia was given as described in General Anesthesia Procedure and wound monitoring occurred as described in Wound Monitoring.

2.11. Study endpoint

The study was terminated when the wound(s) of interest had closed completely or at day 35, whichever occurred first. Animals were euthanized according to American Veterinary Medical Association Guidelines.

2.12. Cryo-sectioning

Wound biopsies used for immunohistochemistry were fixed using OCT compound (Sakura Finetek, Torrance, CA). Samples were sectioned using the Leica CM3050S cryostat at a temperature of −20 °C and thickness of 8 μm and attached to Superfrost-Plus treated glass slides (Thermo-Fisher Scientific, Waltham, MA). Glass slides were stored in a −80 °C freezer prior to immunohistochemistry.

2.13. Immunohistochemistry

2.13.1. Hematoxylin & eosin staining

Fresh frozen sectioned slides were air-dried for up to 30 min. Using Vector Lab’s Hematoxylin and Eosin (Burlingame, CA) staining kit, adequate hematoxylin, bluing reagent, and Eosin Y Solution were applied according to kit instructions. Slides were mounted with a coverslip (Size 24x50-1, Thermo- Fisher Scientific, Waltham, MA), Permount mounting medium (Thermo- Fisher Scientific, Waltham, MA) and left on the heat bench to dry for 1 h.

2.13.2. Primary and secondary antibody staining

Wound biopsy samples were processed for immunohistochemical staining to evaluate the presence of Actin, VEGF-A, and CD-31. Fresh frozen sectioned slides were air-dried for up to 30 min. Immunohistochemistry was performed following standardized protocols. Shandon staining clips (Thermo-Fisher Scientific, Waltham, MA) were used. 1.5% normal blocking serum (Goat serum stock, Vector Labs, Burlingame, CA) diluted in 1X PBS was applied to all slides.

Immunohistochemistry was performed using the following antibodies: Actin, mouse monoclonal, and TNF-A rabbit polyclonal, (Thermo-Fisher Scientific, Waltham, MA), Elastin, mouse monoclonal (Abcam, Cambridge, MA), and PECAM-1, mouse polyclonal (Bio-Rad Laboratories, Hercules, CA). Primary antibodies, PECAM-1, Actin, and TNF-A were diluted 1:200 in 1X PBS per manufacturer protocol. Primary antibody, elastin, was diluted 1:50 in 1X PBS, assay-dependent per manufacturer protocol. The secondary biotinylated anti-mouse and anti-rabbit IgG antibodies (Vector Labs, Burlingame, CA) were diluted 1:200 in 1X PBS. The primary antibody was omitted for control slides. Absence of signal was confirmed using a Leica DM500 microscope.

The Elite ABC HRP stain kit (Vector Labs, Burlingame, CA) was diluted according to kit instructions and left on slides for 30 min 3,3′ diaminobenzidine (DAB) substrate (Vector Labs, Burlingame, CA) was made according to the kit instructions and applied to the slides. The slides were counterstained in Gill’s Hematoxylin stain 2 (Thermo-Fisher Scientific, Waltham, MA) to stain the nuclei.

To dehydrate and clear the tissue sections for mounting, the slides were dipped into progressively more concentrated ethanol and Xylenes (Thermo-Fisher Scientific, Waltham, MA). Lastly, the slides were permanently mounted with Permount mounting medium, cover-slipped and left to dry on the heat bench for 1 h. All images were obtained using a Leica DM2500 light microscope.

3. Data analysis

3.1. Wound geometry measurements

The 3D wound images were analyzed using the QuantifiCare LifeViz software, which accurately monitors changes in wound geometry with minimized inter-rater difference [24]. Wound areas were traced to generate a 3D image of the wound, and wound dimensions calculated by the LifeViz software. Wound volume is calculated relative to the reconstructed skin surface, i.e. where the surface would be if the wound were not present. [25]. These data were used to show changes in wound geometry, from the values measured on monitoring day zero. Images were excluded from analysis if surface reflections caused errors of large ‘spikes’ or ‘craters’ in the 3D generated images. Inter-group differences were determined using Students t-test for independent samples.

3.2. MolecuLight image analysis

MolecuLight fluorescent light images provide a qualitative overview of wound biofilm colonization.

4. Results

4.1. Wound imaging −35mm camera

35 mm camera images were obtained at wound creation and all monitoring days. Fig. 2 shows a typical progression for SoC and actively treated wounds. Wound healing progress can be seen, with the actively treated wound fully healed at monitoring day 28.

Fig. 2.

Fig. 2.

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35 mm wound images showing changes in wound geometry over time.

Images show progressive changes in the size of wounds treated with a functional therapeutic device,(Active) compared to standard of care bandaging (SoC). BTD = baseline to treatment day.

4.2. Wound geometry – LifeViz

Wound perimeter was lower in treated wounds at all timepoints after initiation of treatment (day 0), with significant differences relative to SoC at days 7, 10, 14, and 28 (Fig. 3). Wound volume was lower in treated wounds at all timepoints after day 3, with significant differences relative to SoC at days 7, 14, 17, 23, and 28 (Fig. 4). At day 28, all treated wounds were completely healed.

Fig. 3.

Fig. 3.

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Average wound perimeter captured by LifeViz

Changes in wound perimeter on monitoring days for wounds treated with a functional therapeutic device,(Active) compared to standard of care bandaging (SoC). ignificant differences in wound perimeter are shown as * = p < 0.05.

Fig. 4.

Fig. 4.

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Average wound volume captured by LifeViz

Changes in wound volume on monitoring days for wounds treated with a functional therapeutic device,(Active) compared to standard of care bandaging (SoC). Significant differences in wound volume are shown as * = p < 0.05.

4.3. Wound thermography

Infra-red thermography images were obtained at wound creation and all monitoring days. Fig. 5 shows changes in wound bed temperature over time for SoC and actively treated wounds. There were no significant differences in wound bed temperatures between treatment groups.

Fig. 5.

Fig. 5.

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Wound bed temperature showing changes in wound bed temperature over time.

Changes in wound bed temperature on monitoring days for wounds treated with a functional therapeutic device (Active) compared to standard of care bandaging (SoC).

4.4. Biofilm imaging

MolecuLight:

Moleculight images were obtained from all wounds at every monitoring day to qualitatively identify levels of bacteria presence (red fluorescence) and, specifically, P. aeruginosa (cyan fluorescence) in the wounds. Fig. 6 shows the qualitative fluorescence images.

Fig. 6.

Fig. 6.

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MolecuLight images showing changes in biofilm activity in the wound region.

Images show differences in MolecuLight fluorescence images showing levels of biofilm present in wounds treated with a functional therapeutic device (Active) compared to standard of care bandaging (SoC). BTD = baseline to treatment day.

4.5. Planktonic wound infection

Wound swabs were cultured on blood agar plates. Change in total bacterial load over time, normalized to baseline levels, were determined (Fig. 7).

Fig. 7.

Fig. 7.

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Relative change in planktonic bioburden over time.

Relative changes in planktonic bioburden for wounds treated with a functional therapeutic device (Active) compared to standard of care bandaging (SoC).

4.6. Hematoxylin and Eosin(H&E) staining

H&E staining for sectioned tissue biopsies from SoC and active wounds (Fig. 8) showed differences in tissue structure and reepithelization at the same timepoint. Biopsies were taken from the wound margin and the center of the remaining wound bed.

Fig. 8.

Fig. 8.

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H&E staining of muscle biopsy tissue sections.

Biopsies were taken at the margin and center of wounds treated with a functional therapeutic device (Active) and standard of care (SoC), at the beginning, midpoint, and end treatment timepoints. BTD = baseline to treatment day.

4.7. Immunohistochemistry

Immunohistochemical staining for Actin and VEGF-A showed they were ubiquitously expressed. CD31 marker (Fig. 9) showed variations in angiogenic activity between active and SoC wounds.

Figure 9.

Figure 9.

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Immunohistochemical staining for CD31 in muscle biopsy tissue sections.

Biopsies were taken at the margin and center of wounds treated with a functional therapeutic device (Active) and standard of care (SoC), at the beginning, midpoint, and end treatment timepoints. BTD = baseline to treatment day.

4.8. Wound pH

The presence of bacterial colonization may contribute to the increased pH, allowing pH measurements to be used as a marker of wound healing and a sign of biofilms [26]. Fig. 10 shows the average pH data from wounds over the healing period. The mean wound pH was found to be more variable for SoC wounds on monitoring days from BTD21 on. This may be because the SoC wounds were larger and carrying a greater planktonic bioburden than the actively treated wounds.

Fig. 10.

Fig. 10.

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Wound bed pH showing changes over time.

Changes in wound bed pH on monitoring days for wounds treated with a functional therapeutic device (Active) and standard of care (SoC).

5. Discussion

Electroceutical therapy is the only adjunctive treatment recommended for chronic wound therapy [27]. Electroceutical therapy, simulates the natural bio electrical response to injury [28] by promoting angiogenesis and inducing the migration of endothelial cells to the wound site [29]. Bacterial growth is also inhibited [30], together with disruption of wound biofilms [31]. These well-known effects can synergize to promote healing of chronic wounds using appropriate electroceutical therapy.

A porcine model of large chronic wounds of clinically realistic size was created and utilized to evaluate a wearable electroceutical biotechnology. Wound imaging showed the wound blocks delayed healing for the first 14 days to create a model for a chronic wound (Fig. 2). Wounds were inoculated after wound block removal to provide the infected condition observed in chronic wounds. Multivariate non-invasive assessment was used to monitor wound progression over multiple timepoints.

5.1. Wound geometry

Results showed the treated wound perimeter and volume were significantly lower than SoC by day 7, even though the treated wounds were initially larger (Figs. 3 and 4). Treated wounds were completely healed earlier. This indicates that the application of the active electroceutical therapy increased the rate of wound healing and decreased the time to full healing.

5.2. Wound thermography

On every monitoring day IR data were captured to provide the temperature of the wound. Wound temperature is related to healing, with non-healing, chronic wounds having a higher temperature that decreases during healing [32]. There were no significant differences in temperature between groups, indicating that electrical stimulation (ES) was not altering wound bed temperature (Fig. 5).

5.3. Wound pH

Fig. 7 shows the average pH data from wounds over the healing period. There are no significant differences between groups, indicating that ES was not altering wound bed pH.

5.4. Presence of bacteria

All wounds were inoculated with Pseudomonas aeruginosa on day 0. Standard wound swabs and fluorescent images were captured using MolecuLight on every monitoring day. Total planktonic bioburden was reduced at all timepoints following inoculation in treated wounds, with marked reduction by treatment day 14 and beyond (Fig. 7). The decrease was 1–3 Log CFU greater than for SoC. The fluorescence illuminates bacteria, with P. aeruginosa displaying as cyan colored [33]. Thus, Fig. 6 illustrates the relative presence of bacteria in the wounds. The presence of P. aeruginosa can be observed in treatment and SoC wounds on all monitoring days post-inoculation indicating successful inoculation to simulate chronic wound conditions. It can be seen that the treated wounds appear to have lower amounts of this cyan light, which is in concordance with previous studies showing that electrostimulation can effectively disrupt biofilms and inhibit bacterial growth [30,31].

6. Limitations

Qualitative images of wound healing outcomes provide visual indications of changes over time and inter-group differences. The mCherry fluorescence in the wound from P. aeruginosa RP2229 was not distinguishable from the red fluorescence of the bacterial infection and the intense green fluorescence of the Pseudomonas siderophore, pyoverdine. Quantification was beyond the scope of the current study for histology and MolecuLight imaging.

7. Conclusion

Multivariate data showing increasing rates of wound healing in a chronic wound of clinically relevant size created in a porcine model suggest that a wearable electrostimulation bandage, has the potential to offer therapeutic benefit in human wounds. While this study examined a novel device, these results are in agreement with previous porcine and clinical studies using similar applications of direct current ES which have shown increased wound area reduction [34,35]. The tested device provides the same proven effectiveness of traditional ES therapy while mitigating commonly cited barriers, including substantial time requirements, and availability and complexity of currently available equipment, preventing its implementation in routine wound care [36]. These results are substantiated by the use of a porcine model, which allowed testing of the device on wounds of a clinically realistic size and method of healing. The model responded as expected to inoculation and standard wound care to create a reliable in vivo chronic wound model of large infected wounds that can be of value to others seeking to carry out pre-clinical evaluation of the efficacy of topical wound healing therapies and wearable technologies.

Acknowledgments

The authors would like to thank Joseph Lerchbacker, Jason Collins.

Funding sources

This work was supported by Dept. Of Veterans Affairs Rehabilitation and Research Development Service Merit Award RX002166.

Abbreviations and Acronyms

BTD

baseline to treatment day

CFU

colony-forming unit

ES

electrical stimulation

IR

infra-red

PBS

Phosphate-buffered saline

PIV

peripheral intravenous

SoC

Standard of care

Footnotes

Author disclosure

The authors have no financial interests which may lead to a conflict of interests with regard to the information presented in this paper.

Ghostwriting

No ghostwriters were employed in the preparation of this manuscript.

Declaration of competing interest

The authors have no competing interests to declare.

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