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Keywords:

  • ureter;
  • biodegradable;
  • stent;
  • wounds and injuries;
  • firearms;
  • model;
  • animal

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Study Type – Therapy (case series)

Level of Evidence 4

OBJECTIVE

• To study the operability and effectiveness of a biodegradable ureteral stent for clinical treatment of ureteral war injury using a canine model.

MATERIALS AND METHODS

• A device was designed and employed to generate firearm fragment wounds in unilateral ureters (on randomly chosen sides) of nine beagles (Group A). The wounded ureters were then debrided and sutured.

• Intravenous pyelography (IVP) and radioactive renography were performed 40, 80 and 120 days postoperatively. In Group B, firearm fragment wounds were made to the bilateral ureters in nine beagles. A polylactic acid stent was placed unilaterally (on a randomly chosen side) whereas the ureter on the other side was debrided and sutured without stenting.

• Both IVP and radioactive renography were performed 40, 80 and 120 days postoperatively. The operability and effectiveness of the biodegradable ureteral stent were studied thereafter.

RESULTS

• In Group A, hydronephrosis and hydroureter occurred and worsened postoperatively on the wounded sides in all nine beagles. The ratio of the renal partial concentration indices (RPCI) between the kidneys (unwounded side : wounded side) increased.

• The ratio of the kidney washout half-time between the kidneys (unwounded side : wounded side) decreased. In Group B, neither hydronephrosis nor hydroureter was found postoperatively in the stented ureters but both occurred in the unstented ureters in all nine beagles.

• The ratio of RPCI between kidneys (stented side : unstented side) increased whereas the kidney washout half-time ratio between the stented and unstented sides decreased. Differences were significant.

CONCLUSION

• In Group A, the new canine model for firearm fragment wounds was tested and proved to be operable and effective. In Group B, hydronephrosis and hydroureter were effectively prevented in ureters by biodegradable stent placement compared with the non-stented ureters where hydronephrosis and hydroureter occurred. The renal concentration capacity was effectively protected and the half-time of kidney washout was shortened.


Abbreviation
PLLA

poly-l-lactic acid

PDLLA

poly-dl-lactic acid

IVP

intravenous pyelography

RPCI

Renal Partial Concentration Index

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

When treating ureteral war injuries, ureteral stents are used to hold the ureters open and draining. The most widely adopted stent is the double-J stent [1–3]. However, placement of a double-J stent requires a second procedure for its removal, which is invasive and causes great patient discomfort; in addition, long-term placement of ureteral stents causes many complications, including infection, blockage by encrustations, haematuria, discomfort and calculus [4–8]. Therefore, a biocompatible uereteral stent triggering fewer complications is needed.

With the development of biodegradable polymers and their use for urinary stents [9–16], there has been progress in research on application of polylactic acid for ureteral stents [17–25]. Biodegradable polymers, with greater biocompatibility, can degrade in vivo, which obviates the need for a second procedure for stent removal and has good safety.

The purpose of this research is to discuss the efficacy and feasibility of polylactic acid ureteral stents applied in the canine model for treatment of ureteral war injuries.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

We manufactured a device for generating firearm fragment wounds using home-made firecrackers, cartridge cases (with the base of the cartridge case cut off) and shrapnel (Fig. 1A,B). Firecracker production is uniform: each firecracker contains 3 g black powder (explosion speed 400 m/s), has the same fuse (5 cm) and the same weight (12 ± 0.2 g). Four 7.62-mm calibre cartridge cases (tank machine gun) were connected in series to form the explosive section and two 5.8-mm calibre cartridge cases (type-95 rifle) were connected in series to form the sight section. These two sections were then connected in series. A 12.7-mm calibre cartridge case (anti-material rifle) can be added as a protective handle. Shrapnel is glued to the exit of the sight section. The device works as follows. The firecracker explodes in the first segment of the explosive section and generates shock waves successively through the second, third and fourth segments of the explosive section. These shockwaves pass through the sight section, which has a smaller calibre, and project the shrapnel outwards to generate wounds similar to firearm fragment wounds. The blast damage area and power are controlled (maximum effective range is about 10 cm) and the device is legal in China, a country that has strict gun control laws.

image

Figure 1. A, Three kinds of cartridge cases without base (the base of cartridge case is cut off). B, Configuration of the firearm fragment wound generator. C, Firearm fragment injury inflicted on ureter by shrapnel. D, Histological observation of the wounded ureter tissue after firearm fragment injury: the full thickness of the ureter was torn by the firearm fragment, with haemorrhage at the submucosal layer around the wounds and within the muscular layer. There were residues in the surrounding areas, and a small amount of neutrophil aggregation in minute vessels (haematoxylin & eosin ×40). E, Polylactic acid biodegradable ureteral stent. F, Polylactic acid ureteral stent inserted into the ureter.

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Polylactic acid was provided by the Department of Materials Science and Engineering of Tsinghua University in China. The stent used in this experiment was manufactured using poly-l-lactic acid (PLLA) and poly-dl-lactic acid (PDLLA) mixed together in mass proportion. A 25% barium sulphate additive was applied to the material to enhance its radio-opacity. After the process of mixing, forming, cutting, winding, drying, trimming and 60Co irradiation for sterilization, the cylindrical stent with a spiral and helical design was formed (50 mm length, 0.8 mm inner diameter, 1.4 mm outer diameter) (Fig. 1E). With an expansion rate of 26.80 ± 1.66%, the stent is capable of expanding at the designated location and becoming locked in place. According to in vitro observations, it takes approximately 10 weeks for the hydrolytic degradation process of the stent in canine urine at 37 °C; the biodegradable stent finally degraded to a sand-like substance.

Animal experiments were carried out in the Experimental Animal Centre at the General Hospital of PLA in China. Eighteen beagles ranging from 9 to 11.5 kg were selected. Eight were male and 10 were female. The animals were randomly divided into two groups, Group A and Group B, with nine dogs in each group.

Beagles were anaesthetized with 3% pentobarbital (25 mg/kg) and a tracheal cannula was employed for mechanical respiration. Dogs were placed in a supine position, cut at the hypogastrium and the bladder was found. A mark was made where the ureters met the bladder. The ureter of a beagle is about 15 cm in length and the mid-ureter (7 cm from the ureterovesical orifice) was selected as the location where injuries were to be made.

Group A was used to develop the canine model of ureteral war injury. The firearm fragment injuries were made to unilateral ureters on the randomly chosen side (Fig. 1C). Then, wounds were wrapped in wet gauze and left for 30 min. After that, debridement was performed. The injured segment (1 cm) of ureter was cut off for pathological examination (Fig. 1D) and two pieces of 6-0 absorbable sutures were used for end-to-end anastomosis to restore ureteral continuity. The ureters on the opposite side remained intact.

Group B was used for observing the role of the biodegradable stent in the treatment of ureteral firearm injuries. Firearm injuries were made to ureters at the same position as in Group A but on both sides. A process of debridement, cutting the wounded site, and suturing was conducted in exactly the same way as in Group A on one randomly chosen side. The ureters on the other side were selected for biodegradable stent placement (Fig. 1F). The stent’s mid-point was positioned exactly where ureteroureterotomy had been performed, and the stent was fixed at the site of anastomosis with 6-0 absorbable sutures.

Conventional drainage and abdominal closure were performed, and both replacement of wound dressing and anti-infection treatment were provided postoperatively. Sutures were removed after 1 week. All surgery was performed by the same surgeon.

One week preoperatively and 40, 80 and 120 days postoperatively, all of the beagles underwent intravenous pyelography (IVP) and renogram. At 40, 80 and 120 days postoperatively, three beagles from Group A and three from Group B were randomly selected and killed by overdose of anaesthesia after the examination.

Quantitative renogram analysis indicators were processed by one-way anova using the SPSS 13.0 software (SPSS, Chicago, IL). Values of P < 0.05 were taken to be significant and the results are given as mean ± SD.

All animal experimental protocols were approved by the committee of animal research at the PLA General Hospital and the procedures were performed in accordance with guidelines for humane handling of animals.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

All beagles survived the procedures and stayed alive until they were killed.

After the firearm fragment wound, the injured segment (1 cm) of ureter was cut off for pathological examination. At the location of the wound, the full thickness of the ureter was completely torn by the firearm fragment, with haemorrhage in the submucosal layer around the wounds and within the muscular layer. There were residues in the surrounding area and a small quantity of neutrophil aggregation in minute vessels (Fig. 1D). In the area confused and shockwave stricken, haemorrhage was found in the submucosal layer and within muscular layers; part of the epithelium had become detached. Our results were consistent with the pathological performance of a firearm fragment wound.

In Group A, the preoperative IVP showed no hydronephrosis or hydroureter at the bilateral renal pelvis or ureters. Postoperatively, renal pelvis and ureter on the unwounded side were normal. But both hydronephrosis and hydroureter occurred on the wounded side and becamse worse with time.

The quantitative renogram analysis in Group A used the Renal Partial Concentration Index (RPCI) and the half-time of kidney washout as indicators. The RPCI reflects the effective plasma flux in the kidney as well as the speed of uptake and the amount of tracer taken in by the renal tubular epithelium. The kidney washout half-time is an indicator of how much tracer in urine is washed out from the kidneys and at what speed. This is linked with the volume of urinary flow and whether the urinary tract is obstructed or not. Though RPCI and half-time of kidney washout are indicators in quantitative renogram analysis, they are affected by several factors such as the body plasma volume. Values of those factors vary significantly when measured at different time points, causing wide inaccuracy. However, these system errors are deemed to be undiscriminating between kidneys on both sides. For this reason, when comparing the results of preoperative and postoperative renograms, we used the ratio of RPCI between bilateral kidneys (left side : right side) and the ratio of half-time of kidney washout between bilateral kidneys (left side : right side), which will eliminate the system errors and ensure accuracy.

At 1 week preoperatively and 40, 80 and 120 days postoperatively, the RPCI ratio of bilateral kidneys (unwounded side : wounded side) increased gradually (1.056 ± 0.175, 1.270 ± 0.209, 1.523 ± 0.211, 1.894 ± 0.213; F = 15.920, P= 0.000). Differences were significant (Fig. 3A). The ratio for the half-time of kidney washout (unwounded side : wounded side) decreased gradually (1.023 ± 0.101, 0.924 ± 0.100, 0.726 ± 0.130, 0.550 ± 0.126; F = 18.347, P= 0.000) and differences were again significant (Fig. 3B).

image

Figure 3. Renogram quantitative analysis. A, Ratio of renal partial concentration indices (RPCI) (unwounded side : wounded side) in Group A. B, Ratio of half-time of kidney washout (unwounded side : wounded side) in Group A. C, Ratio of RPCI (biodegradable stent side : unstented side) in group B. D, Ratio of half-time of kidney washout (biodegradable stent side : unstented side) in group B.

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In Group B preoperatively, no hydronephrosis or hydroureter was found on either side (Fig. 2A). At 40 days postoperatively, the biodegradable stents remained in good shape and position; partial degradation was found 80 days postoperatively (Fig. 2C). At 120 days postoperatively, the stent degraded and was washed out almost completely, with a few fragments left in the ureters (Fig. 2E). At different times postoperatively, no hydronephrosis or hydroureter was found on the sides where biodegradable stents were placed; drainage was prompt; the junction where ureter met bladder was clear. In contrast, on the wounded side where only debridement and suturing were performed without stent, both hydronephrosis and hydroureter occurred and worsened with time (Fig. 2B,D,F).

image

Figure 2. Plain abdominal radiograph of kidney-ureter-bladder (KUB) and intravenous pyelography (IVP) of Group B before and after operation (white arrows indicate the biodegradable stent). A, Preoperative IVP, the image was clear and no hydronephrosis or hydroureter was found in bilateral renal pelvis and ureter. B, IVP at 40 days postoperatively: the biodegradable stents remained in good shape and position. Slight hydronephrosis could be seen on the other side. C, KUB at 80 days postoperatively: partial degradation of the stent is visible. D, IVP at 80 days postoperatively: no hydronephrosis on the side with the stent but moderate hydronephrosis on the other side without the stent. The junctions where ureters meet bladder were clear on both sides. E, KUB at 120 days postoperatively: the stent has degraded almost completely with a few fragments left in the ureters. F, IVP at 120 days postoperatively: no hydronephrosis on the side with stent but severe hydronephrosis on the other side without stent.

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At 1 week preoperatively and 40, 80 and 120 days postoperatively, the RPCI ratio of bilateral kidneys (stented side : unstented side) increased gradually (0.994 ± 0.114, 1.239 ± 0.220, 1.574 ± 0.315, 1.553 ± 0.275; F = 9.986, P= 0.000). The differences were significant (Fig. 3C). The ratio of the half-time of kidney washout ratio (stented side : unstented side) decreased gradually (1.058 ± 0.169, 0.863 ± 0.121, 0.716 ± 0.0638, 0.655 ± 0.120; F = 11.656, P= 0.000). The differences were significant (Fig. 3D).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

The ideal ureteral stent should be functional (holding the ureters open and allowing drainage); besides, it should incorporate properties featuring good biocompatibility, anti-infection, anti-encrustation and patient comfort. Currently there is no such stent incorporating all these properties so people are studying the material, design and coating for biodegradable stents [26–29].

In recent years, there has been continual progress in research and development of biodegradable stents. Healing the transverse cut on beagles by applying a self-expandable, self-reinforced poly-l,d-lactide partial ureteral stent (SR-PLA 96) reveals that stent tube does not affect urinary tract dynamics; and the stent’s tissue compatibility is almost equal to that for double-J stent, preventing the reflux where ureters meet bladders [20–22]. In one study, a temporary ureteral drainage stent was applied to percutaneous nephrolithotripsy. The temporary ureteral drainage stent achieves prompt drainage, attaining good patient comfort with only a few patients feeling mild discomfort. The complication rate is low and the surgery is safe [24,25]. However, disappointing results are obtained with poly l(-)lactic acid biodegradable ureteral grafts as an alternative treatment for agenesis of ureter. Because of hydrolytic degradation and fragments lodging in the ureters, kidney dysfunction may occur [17]. After endopyelotomy, disappointing results are obtained using poly-l-lactide-co-glycolide stents. The fragments lodged in the surrounding tissues of the ureters, and the ureteral muscle where ureterotomy had been performed healed poorly [23].

Our research group applied the biodegradable stents to treat urethrostenosis [14–16] and biliary tract injury [30], achieving encouraging results. The research, based on a canine model, further discussed the feasibility and efficiency of applying biodegradable stents to treat ureteral war injuries.

According to the war records since World War II [31–34], ureteral injuries are caused mainly by firearm fragments. Therefore, the research group, inspired by the positioned explosion generator [14], made a simple device (using home-made firecrackers and lipless cartridge cases) for generating firearm fragment wounds. Although of simple design, the device successfully simulated the actual process of generating a firearm fragment. The beagles were untreated for 30 min after injury because it takes about 30 min for wounded soldiers to be transferred from the battlefield to division aid stations or a field hospital for treatment [31]. We then followed the principle of conventional treatment for ureteral firmament injury, debridement and suturing of the wounds to restore the continuity of the ureters.

In Group A, during postoperative healing, inflammation occurred where the ureteroureterostomy had been performed, because of the shockwave bruise to surrounding tissues, pollution by firearm fragments and gunpowder, damage caused by the wound-cleansing process, and irritation caused by gunpowder residues, sand soil and absorbable suture. Secondary hyperplastic scars grew and ureterostenosis worsened.

According to the IVP, hydronephrosis and hydroureter were found where ureteroureterostomy had been performed and the situation deteriorated with time. Images proved that hyperplastic scar and ureterostenosis had formed where ureteroureterostomy had been performed. According to the quantitative renogram analysis, compared with the unwounded side, the RPCI at the wounded side decreased sharply throughout the study, and the half-time of kidney washout rose significantly. From the perspective of kidney function, this proves that hydronephrosis on the wounded side where ureteroureterostomy had been performed weakened renal concentration and prolonged excretion of urine. These findings showed that the beagle model of firearm fragment wounds efficiently simulated the generation of a firearm fragment wound and the subsequent processes.

In Group B, where the beagles’ ureters were injured on both sides, the ureters on one side had stents inserted whereas the ureters on the opposite side did not. In this way, the biodegradable stents’ contribution to healing could be revealed.

According to the IVP, both hydronephrosis and hydroureter were found on the unstented side and worsened with time. On the stented side, no hydronephrosis or hydroureter was found, proving that the biodegradable stents are efficient for holding the ureters open and allowing drainage; besides, biodegradable stents efficiently prevented hydronephrosis and hydroureter by protecting the ureters against ureterostenosis. As KUB reminded, 40 days postoperatively, the biodegradable stents remained in position without any degradation, which met the demand for stability and mechanical strength during the early healing stage. At 80 days postoperatively, the stents began to degrade rapidly; by 120 days, only a few fragments were found in the uereters. This proved that the stents degraded after accomplishing their task of holding the ureters open and draining, eliminating the need for stent removal procedure.

The quantitative renogram analysis showed that, compared with the unstented side, the RPCI kept increasing gradually and the half-time of kidney washout kept decreasing on the stented side. The differences were significant proving that biodegradable stents are efficient in holding ureters open and allowing drainage. Biodegradable stents are capable of preventing obstruction in the upper urinary tract, hydronephrosis, and prolonged excretion of urine.

Polylactic acid ureteral stents can be used in the treatment of ureteral war injuries. These stents are reliable in holding ureters open and allowing drainage, preventing hydronephrosis, and maintaining the kidneys’ normal function. They also degrade and are washed from the body. They therefore, represent a promising future for treatment of ureteral war injuries.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

This study was supported by the Eleventh Five-year subject of the surface of the whole army project funded projects (No. 06MA298); Beijing Natural Science Foundation (No. 2092029) and Scientific and technological innovation and nursery Fund of the general hospital of PLA (No. 08MP-08). We are grateful to Professor Jia Yingxin, a firearms and explosives expert from the Military Department of the Academy of Armoured Force Engineering, who helped us to manufacture the device for generating firearm fragment wounds.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES