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Novel gastric sleeve magnetic implant: safety and efficacy in rats
Surgery for Obesity and Related Diseases 5 (2009) 684 – 691
Original article
Novel gastric sleeve magnetic implant: safety and efficacy in rats Xiaomei Guo, M.D.a, Samer Mattar, M.D.b, Celina Morales, M.D.c, Jose A. Navia, M.D.d, Ghassan S. Kassab, Ph.D.a,b,e,* a
Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana b Department of Surgery, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana c Department of Pathology, University of Buenos Aires, Buenos Aires City, Argentina d Department of Surgery, Austral University, Buenos Aires City, Argentina e Department of Cellular and Integrative Physiology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana Received January 22, 2009; revised June 19, 2009; accepted July 30, 2009
Abstract
Background: The prevalence of obesity is growing worldwide and has reached epidemic proportions. Vertical sleeve gastrectomy, which requires irreversible removal of gastric tissue, is considered an effective weight loss treatment of severe obesity. The aim of the present study was to evaluate the feasibility of a reversible gastric sleeve magnetic implant that mimics the vertical sleeve gastrectomy without the gastrectomy for weight loss in a group of normal and obese rats. Methods: A group of Zucker fatty rats either underwent surgical implantation or a sham operation and were followed up for 6 weeks. Also, a group of Wistar rats underwent surgical implantation for 6 weeks, followed by surgical implant removal at 6 weeks, and recovery for an additional 4 weeks. Food intake and body weight were monitored after surgery to determine the efficacy of the device. A histologic examination for all rats was made to evaluate the change in the gastric wall in response to gastric sleeve magnetic implantation. Results: The implanted Zucker fatty and Wistar rats showed a statistically significant decrease in food intake and weight gain rate compared with the sham-operated rats (approximately 3%/wk of body weight loss in the treated group). Moreover, the decrease in the weight gain rate was sustained for 4 weeks after removal of the magnetic implant. The histologic evidence revealed an inflammatory mononuclear cell infiltration and mild fibrosis and hyperplasia of blood vessels, as expected for any implant. No significant structural damage, tissue ischemia, hemorrhage, or necrosis was found in the gastric wall. Conclusion: Our results have shown that the device is feasible in rats, results in effective weight loss, and can be easily removed. These findings, along with the lack of the need for resection of the native stomach, provide a compelling basis for additional development of the device in large animal models. (Surg Obes Relat Dis 2009;5:684 – 691.) © 2009 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Obesity; Vertical sleeve gastrectomy; Magnetic implant; Food intake; Body weight
Obesity has become a major health problem in the industrialized world during the past few decades [1,2]. The World Health Organization has estimated that ⬎1.6 billion adults (age ⱖ15 years) are overweight and ⱖ400 million are *Reprint requests: Ghassan S. Kassab, Ph.D., Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202. E-mail: [email protected]
considered obese [3]. Obesity increases the risk of diabetes, stroke, hypertension, heart disease, kidney disease, gallbladder disease, osteoarthritis, and depression [4,5]. Weight loss has been found to improve or resolve these co-morbidities [6 – 8]. Of the available therapeutic modalities, bariatric surgery has been found to be the most effective and durable treatment of morbid obesity. In response, interest has been increasing in the surgical treatment of morbid obesity. Bariatric surgery (e.g., Roux-en-Y gastric bypass, adjustable
1550-7289/09/$ – see front matter © 2009 American Society for Metabolic and Bariatric Surgery. All rights reserved. doi:10.1016/j.soard.2009.07.005
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gastric banding, vertical sleeve gastrectomy [VSG]), by restrictive or malabsorptive methods, is the only current treatment capable of sustaining profound weight loss [6,9,10]. VSG has gained significant interest as a definitive bariatric operation in the past decade. It provides superior weight loss results, with an acceptable safety profile, at least in short-term follow-up studies, because follow-up data ⬎5 years are not yet available [11–13]. The sleeve is created by placing a vertical staple line and removing the remaining 85% of the stomach, to leave a long banana-like pouch. The VSG generates weight loss solely through a marked reduction of hunger and a reduced gastric capacity, but without malabsorption. Changes in the gastrointestinal hormonal levels have been proposed to contribute to the mechanism of weight reduction after bariatric surgery [14 –17]. The possible hormonal mechanisms involved in sustainable weight loss are still debated [14 –16,18]. Despite the efficacy, the current VSG procedures have several limitations, including the risk of staple line leaks and late complications, such as weight regain with gastric sleeve dilation. Moreover, longterm (⬎5 years) outcomes are still pending [12,19 –21]. In addition, the gastric sleeve is not reversible. To mimic the benefits of VSG without some of the shortcomings, we have proposed a VSG-like device termed the “gastric sleeve magnetic implant” (GSMI). The device uses permanent magnets to form the line of restriction, rather than surgical staples and gastrectomy, such as in the VSG procedure. The objective of the present study was to evaluate the feasibility of the reversible GSMI for weight loss in the Zucker fatty and Wistar rats. Methods Rats A total of 35 Zucker fatty rats, 14 –15 weeks old, and 12 healthy Wistar rats, 12–13 weeks old (Charles River Laboratories, Wilmington, MA) were used in the present study. Group 1 (18 Zucker fatty rats) underwent GSMI placement for a 6-week period and was killed at the end of the 6 weeks. Group 2 (17 Zucker fatty rats) served as the sham-operated controls for group 1. They underwent an identical surgical procedure, except without the actual implantation, and were also killed at the end of the 6 weeks. Group 3 (7 Wistar rats) underwent GSMI placement for a 6-week period but were allowed to recover for 4 weeks after implant removal. Group 4 (5 Wistar rats) was used as the sham-operated control for group 3. All animal experiments were performed in accordance with national and local ethical guidelines, including the Institute of Laboratory Animal Research guidelines, Public Health Service policy, the Animal Welfare Act, and an approved University of Indiana-Purdue University Indianapolis protocol regarding the use of animals in research.
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Surgical procedure All rats were maintained in individual cages with controlled temperature (21–23°C), humidity, and light (12 hours light and 12 hours dark), with free access to commercial standard rat chow and tap water. The food intake was recorded daily for 1 week. Each rat was weighed before each surgical procedure. Surgical implant After a 12-hour overnight fast, the rat was anesthetized with intraperitoneal ketamine (100 mg/kg) and xylazine (8 mg/kg). An abdominotomy (about 2 cm) was performed on the ventral midline. Gauze moistened with sterilized saline was placed around the incision. The stomach was then pulled out gently and placed on the gauze. A continuous 5-0 polypropylene suture was used to suture the front and back walls of the rumen (fibrotic portion of the stomach) together along the limiting ridge, a low fold of tissue that separates the rumen and corpus. The corpus (glandular portion) of the stomach was left intact. Additional interrupted stitches were used to reinforce the external wrap, as needed (Fig. 1). One disk magnet jacketed with a polyurethane sleeve (size 10 mm ⫻ 6 mm ⫻ 2 mm; Br 1500 Gauss) was then placed on the posterior surface of stomach to create a small stomach pouch and an outlet. Another disk magnet (size 10 mm ⫻ 4 mm ⫻ 2 mm; Br 1500 Gauss) with 4 standoff pins (length ⬃4 mm, about the thickness of the 2 walls of the stomach) was longitudinally placed on the anterior surface of the stomach along lesser curvature (Fig. 1). This created a diameter of the sleeve of about 5 mm (distance to the lesser curvature). Because the 2 magnets attracted each other, the pins or 2 staples (standard titanium staples) penetrated the gastric wall and locked into the back magnet, exterior to the stomach. The pins not only prevented overcompression of stomach, but they also prevented the magnets from migrating laterally along the surface of the stomach. The space between the 2 magnets contained lightly compressed gastric wall (the length of a pin was approximately the thickness of the “sandwiched” tissue; i.e., twice the wall thickness). For the sham-operated groups (groups 2 and 4), the rumen was also sutured, as described for the experimental group. Only the disk magnet with 4 standoff pins penetrating the anterior wall was sutured to the surface of the stomach. The stomach was then placed back into the abdomen, and the muscle and skin were closed. Terminal studies of Zucker rats The Zucker fatty rats (groups 1 and 2) were fasted overnight. The rats were killed by administration of an overdose of ketamine and xylazine. The stomach was excised immediately and fixed for later histologic evaluation.
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stomach was carefully removed, and the stomach was pulled back into the abdomen. The anterior disk magnet was left in the abdomen. For the sham-operated group (group 4), the stomach was only pulled out gently and then placed back into the abdomen. The Wistar rats were killed at 10 weeks— 4 weeks after implant removal. The surgical procedure was identical to that described for the Zucker fatty rats. Food intake and weight change After the first 12 hours of fasting after surgery, the Zucker fatty and Wistar healthy rats were given the same standard food chow and water. Food intake was measured daily for the first 2 weeks and then every 2 days for the remainder of the study. The rats’ body weight was measured weekly after surgery. The weight gain rate was defined as weight gain rate in percentages ⫽ [(body weight ⫺ initial weight)/initial weight] ⫻ 100%. Histologic evaluation At death, the gastric tissue immediately below the implant, as well as the tissue adjacent to the implant, for both the Zucker fatty and the Wistar rats was harvested and fixed with 10% formalin in phosphate buffer for at least 10 hours. The sample was then embedded in J-B4 resin and crosssectioned at 3 m thickness. The tissue samples were stained with hematoxylin and eosin and trichrome Masson and examined under a light microscope. Statistical analysis The results are presented as the mean ⫾ standard deviation, and the significance of differences between 2 groups was evaluated using 2-way analysis of variance. The results were considered statistically significant at P ⬍.05 (2-tailed). Fig. 1. Magnetic implantation in rat stomach. (A) Two magnetic clamp halves (1 anterior and 1 posterior) deployed on either side of stomach pouch. Pins between magnetic halves served to maintain distance to prevent stomach compression. (B) Sleeve diameter created by magnetic implants around 5 mm (distance to lesser curvature). Rumen wrapped with suture.
Implant removal Because the Zucker fatty rats are severely sick animals with hypercholesterolemia, hyperinsulinemia, hypertriglyceridemia, hyperlipidemia, and the metabolic syndrome and eventually develop serious cardiovascular diseases and other complications [22–26], they would have been too weak to undergo a second procedure for removal of the device. Thus, a group of normal Wistar rats was used to evaluate implant removal. Anesthesia, sterility, and preparation remained the same as described for implantation. An abdominotomy (about 2 cm) was performed on the ventral midline. The stomach was pulled out gently and placed on gauze. The disk magnet placed in the posterior surface of
Results We only considered the Zucker fatty rats that survived (n ⫽ 20) the surgical procedure without any postoperative complications. Of the 35 Zucker fatty rats, 15 were excluded from analysis because of different postoperative complications: 2 anesthetic deaths, 2 wound infections, 1 case of gastric bleeding, 2 with implant intragastric migration, and 8 with heart failure (substantial ascites and cardiac hypertrophy). All 12 Wistar rats that underwent surgical implantation and implant removal recovered successfully and survived until the termination date. The baseline mean body weight was comparable in the 2 groups of each type of rat before treatment. For the Zucker fatty rats, the mean body weight was 575.3 ⫾ 35.1 g in the experimental group and 551.5 ⫾ 28.4 g in the sham-operated group (P ⫽ .83). For the Wistar rats, the mean body weight was 421.7 ⫾ 55.2 g in the experimental and 420.2 ⫾ 44.5 g in the sham-operated rats (P ⫽ .98).
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The food intake was measured daily and summed for the week. Fig. 2A shows that the food intake was initially reduced in the first postoperative week and then recovered after 2 weeks in both the experimental and the sham groups for the Zucker fatty rats. The food intake was significantly lower in the experimental group than in the sham group throughout the 6-week period (P ⬍.05). The animal body weight was measured weekly after the surgical procedure. In line with the reduced food intake, the weight gain rate was reduced during the first weeks after surgery (Fig. 2B). Thereafter, the weight gain rate was significantly lower in the experimental group compared with that for the sham group (P ⬍.01). The change in food intake for the Wistar rats that underwent implant removal was similar to that of Zucker fatty rats (Fig. 3A). The food intake in the experimental group was significantly less than that for the sham-operated group during the 6-week period (P ⬍.05). The decrease in food intake in week 7 was not statistically significant for either group after implant removal. Subsequently, the significant decrease in food intake in the experimental group was sustained in weeks 8 –10 (P ⬍.05). Fig. 3B shows the weight gain rate for the experimental group was significantly decreased compared with that for the sham-operated group (P ⬍.05). Similarly, no difference in the weight gain rate was observed between the experimental and sham groups in week 7. In the subsequent 3 weeks, however, the
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Fig. 3. (A) Food intake and (B) weight gain rate in experimental and sham-operated Wistar rats for 10 weeks after implant surgery and implant removal. Arrow indicates implant removal at week 6. Food intake and weight gain rate significantly lower in experimental than in sham-operated rats at every week after surgery (P ⬍.05), except for seventh week owing to influence of surgery.
weight gain rate was still lower in the experimental group than that in the sham-operated group (P ⬍.05). We evaluated the stomach of the Zucker fatty rats at 6 weeks and of the Wistar rats at 10 weeks after surgical implantation and found no gross changes in the submucosa or mucosa, and no tissue ischemia or necrosis (Fig. 4). Typically, a fibrotic capsule had formed around the magnet
Fig. 2. (A) Food intake and (B) weight gain rate in experimental and sham-operated Zucker fatty rats for 6 weeks after implant surgery. Food intake and weight gain rate were significant lower in experimental than in sham rats at each week after surgery (P ⬍.05).
Fig. 4. Gastric mucosa after removal of implant showing normal tissue without inflammation, adhesion, or necrosis.
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Discussion
Fig. 5. (A) Removal of posterior magnet after incision of capsule that formed around magnet at end of 6 weeks of surgical implantation in Wistar rats. (B) Pseudocapsule after implant removal showing normal tissue without inflammation or necrosis.
within a few days. This capsule could be easily excised to remove the magnet (Fig. 5). Examination of the JB-4 resin sections under light microscopy showed that the surface columnar cells and gastric glands were undamaged in both the Zucker fatty and the Wistar sham-operated rats (Fig. 6A,B). The ratio of stroma to glands was normal. The implant caused mild vascular ectasia with infiltration of the inflammatory cells (lymphocytes and fibroblast) in the submucosa, muscular layer, and serosa. For the Zucker fatty and Wistar experimental groups, the histologic examination found that the basic architecture of the columnar epithelium after magnetic implant was unaltered (Fig. 6C,D). The gastric glands exhibited mild fibrosis in the lamina propria close to the mucosa with the appearance of scattered inflammatory cells (lymphocytes and fibroblasts). The density of the connective tissue in the mucosa and serosa region had increased. Small hyperplasia of the arteries in the muscular layer was seen with evident venous dilation. Granulation tissue was also present in the serosa region.
Bariatric surgery is the most effective treatment of severe obesity, because it allows sustained weight loss and improves most of the co-morbidities associated with the disease [6]. VSG has been used for the surgical treatment of morbid obesity in humans [14,27], and the results have been very promising. In the present study, a VSG-like device, the GSMI, was used to reduce the gastric capacity and hence lead to diminished food intake. This was accomplished without the need for gastrectomy and could be easily dismantled. It is well known that significant differences exist in the anatomy of the stomach between humans and rats. The rat stomach has a rumen (thin-walled, nonglandular section that forms two fifths of the stomach) that is directly connected to the esophagus. It serves as a holding chamber for food and perhaps a pouch for the esophagus, instead of a true stomach. In theory, suturing off the rumen might diminish the gastric capacity and result in a reduction in food intake. It has been conformed that a prosthetic external wrap of the folded stomach produces weight loss in humans [28]. Nevertheless, in the present study, to best approximate the anatomy of the human stomach and minimize the possible influence produced by the rumen, we sutured off this anatomic structure in both the experimental and the shamoperated groups. We found significant differences between the treated rats and sham-operated controls with regard to both food intake and body weight. The food intake was significantly lower for the experimental group compared with the sham-operated group during the 6 weeks of implant (Fig. 3A). On average, the food intake was reduced by 18.2%/wk compared with the sham-operated rats 1 week after surgery. Because the Zucker fatty rats at 15 weeks of age are still growing, we did not expect to observe a decrease in the absolute body weight but rather a decrease in the weight gain. After bariatric surgery with GSMI placement, the Zucker fatty rat exhibited a significant decrease in the weight gain rate compared with the sham-operated group (Fig. 3B). On average, the weight gain rate was decreased by 15.8% during the 6-week period (2.9%/wk). Recently, Pereferrer et al. [29] reported that sleeve gastrectomy had a slight effect on food intake and body weight in Zucker fatty rats. When corrected for age, the excess weight loss in these rats was reported as 7.3% after 3 weeks of sleeve gastrectomy. de Bona Castelan et al. [30] studied sleeve gastrectomy in Wistar rats and found that both the sleeve gastrectomy and the control group gained weight throughout the 7 postoperative weeks. In the VSG group, however, this weight gain was significantly lower than that in the control group. Our data on the GSMI suggest similarly positive results in the reductions in food intake and weight gain rate. Unlike the VSG, the GSMI can be easily dismantled. The effect of implant removal was evaluated in Wistar rats in the present study. In general, the food intake and body weight
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Fig. 6. Histologic images of gastric wall in response to magnetic implant in (A,B) sham-operated and (C,D) experimental groups for both Zucker fatty and Wistar rats. Trichrome Masson staining, original magnification ⫻400. (A) Gastric mucosa from sham-operated Zucker fatty group. No histological damage seen in surface epithelium, gastric pits, or gastric glands. (B) Gastric glands, mucosa, and submucosa from sham-operated Wistar group. Implant caused mild vascular ectasia with infiltration of inflammatory cells (lymphocytes and fibroblasts) in submucosa, muscular layer, and serosa. Gastric glands (Bottom right) were normal. (C) Gastric mucosa from experimental Zucker fatty group. No histologic damage seen in simple columnar epithelium or gastric glands. Blood vessels in mucosa layer revealed mild vascular ectasia. (D) Gastric glands, mucosa, and submucosa from experimental Wistar group. Gastric glands near mucosa exhibited mild fibrosis with appearance of scattered inflammatory cells (Top right). Moderate fibrosis and venous dilation were also present (Left). Small arteries with vascular ectasia were seen in mucosa layer (Middle).
decreased in the first postoperative week owing to the surgical trauma induced by the surgical implant and removal. During the 6 weeks after surgical implant, the food intake and weight gain rate were significantly lower in the experimental group than in the sham-operated group (Fig. 3). On average, the weight gain rate decreased by 14.6% during the 6-week period. The decrease in food intake and weight gain rate was maintained in the experimental group but not in the sham group at 4 weeks after implant removal. The decrease in the weight gain rate in the experimental group was maintained at 12.9% during the 10-week period. Evidence is growing that bariatric surgery can influence the systems that regulate appetite and satiety [14,15,31,32]. Because the present experiments focused on the feasibility of the surgical implant and implant removal, we could not provide a mechanistic explanation for the sustainability of the weight gain rate after implant removal. Future follow-up regarding long-term weight loss maintenance and a prolonged influence on metabolism is necessary. The Zucker fatty rat was selected as the experimental model because it is a spontaneous genetic model of obesity that exhibits hyperphagia, hyperinsulinemia, and hyperlipidemia [22–24], which better replicates most of the features observed with human obesity. However, we found that the
Zucker fatty rats had high morbidity and mortality rates (35%) in the present study. It has been reported that Zucker fatty rats die rapidly after 9 months of follow-up, with a mortality rate of 64% in the absence of any surgical intervention. The shortened lifespan mainly results from the development of severe renal failure [25]. Grosfeld et al. [33] found that Zucker fatty rats undergoing jejunoileal bypass were more fragile and prone to die, with a 33% mortality rate compared with normal rats. A recent study by Marsh et al. [26] using the Zucker fatty and Zucker diabetic fatty rat models showed unexpectedly high mortality rates shortly after the creation of aortocaval fistula. The deaths were thought to relate to a high incidence of renal and cardiac dysfunction. Our results, coupled with these cited studies, suggest that the Zucker fatty rat is not an appropriate model for a surgical procedure or a long-term study owing to the renal and cardiovascular morbidity and mortality. One common complication seen in the VSG is a leak at the staple lines of the stomach, resulting in infection [12]. No leakage and/or laceration, leading to intraperitoneal infection, caused by the pins of the magnet penetrating both walls of the stomach was observed in any Zucker fatty or Wistar rats in our study. It is plausible that because of the contraction of the gastric smooth muscle, the small incision
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on the stomach wall by the pins (staple with 0.4 mm diameter) closed after surgical implantation, and thus, no leak at the pin sites was observed. We found only 3 cases of postoperative complications directly caused by the device. One Zucker fatty rat died of gastric bleeding 24 hours after surgical implantation because of inadvertent puncture of a large artery around the area of the lesser curvature by the pins. More careful inspection before deploying the device can prevent this incident. Two rats with intragastric migration survived and had no obvious symptoms until death. The pathologic necropsy findings showed that the 2 magnets were closed together end-to-end, resulting from a device imbalance. The gastric wall between the 2 magnets was overcompressed, and 1 end of the 2 magnets had gradually migrated into the stomach. This problem arose from the size of the magnetic plates for the rat studies because they can easily tilt. The device for large animal studies is much more stable. To determine the influence of the magnetic implant on the stomach wall, we evaluated the histologic changes in the gastric wall. The histologic findings in the experimental and sham groups for both the Zucker fatty and the Wistar rats were similar (Fig. 6). The most prominent and persistent change from the mucosa to the serosa layer induced by the magnetic implant was a scattered inflammatory mononuclear cell infiltration and mild fibrosis and hyperplasia of blood vessels, as expected for any implant. No evidence was seen of hemorrhage, necrosis, or thrombosis in the gastric wall proximally or distally to the magnetic implant. Our histologic findings have indicated that the GSMI implant maintains the histologic architecture of the stomach in both fatty Zucker and Wistar rats.
Conclusion The results of our study have shown that the GSMI significantly decreases food intake and body weight gain in Zucker fatty and healthy Wistar rats. Furthermore, the reduction in the weight gain rate was sustained for 4 weeks after implant removal. Our results have verified that the GSMI device is feasible and can be removed easily after implantation in the rat model. We have no doubt that a reversible, cost-effective implantable device that maintains the normal anatomic configuration of the overall stomach with effective weight loss would be of significant interest to both patients and surgeons in the fight against obesity. Additional evaluation of the long-term safety and efficacy of the GSMI in larger animals is needed.
Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article.
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Original article
Novel gastric sleeve magnetic implant: safety and efficacy in rats Xiaomei Guo, M.D.a, Samer Mattar, M.D.b, Celina Morales, M.D.c, Jose A. Navia, M.D.d, Ghassan S. Kassab, Ph.D.a,b,e,* a
Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana b Department of Surgery, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana c Department of Pathology, University of Buenos Aires, Buenos Aires City, Argentina d Department of Surgery, Austral University, Buenos Aires City, Argentina e Department of Cellular and Integrative Physiology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana Received January 22, 2009; revised June 19, 2009; accepted July 30, 2009
Abstract
Background: The prevalence of obesity is growing worldwide and has reached epidemic proportions. Vertical sleeve gastrectomy, which requires irreversible removal of gastric tissue, is considered an effective weight loss treatment of severe obesity. The aim of the present study was to evaluate the feasibility of a reversible gastric sleeve magnetic implant that mimics the vertical sleeve gastrectomy without the gastrectomy for weight loss in a group of normal and obese rats. Methods: A group of Zucker fatty rats either underwent surgical implantation or a sham operation and were followed up for 6 weeks. Also, a group of Wistar rats underwent surgical implantation for 6 weeks, followed by surgical implant removal at 6 weeks, and recovery for an additional 4 weeks. Food intake and body weight were monitored after surgery to determine the efficacy of the device. A histologic examination for all rats was made to evaluate the change in the gastric wall in response to gastric sleeve magnetic implantation. Results: The implanted Zucker fatty and Wistar rats showed a statistically significant decrease in food intake and weight gain rate compared with the sham-operated rats (approximately 3%/wk of body weight loss in the treated group). Moreover, the decrease in the weight gain rate was sustained for 4 weeks after removal of the magnetic implant. The histologic evidence revealed an inflammatory mononuclear cell infiltration and mild fibrosis and hyperplasia of blood vessels, as expected for any implant. No significant structural damage, tissue ischemia, hemorrhage, or necrosis was found in the gastric wall. Conclusion: Our results have shown that the device is feasible in rats, results in effective weight loss, and can be easily removed. These findings, along with the lack of the need for resection of the native stomach, provide a compelling basis for additional development of the device in large animal models. (Surg Obes Relat Dis 2009;5:684 – 691.) © 2009 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Obesity; Vertical sleeve gastrectomy; Magnetic implant; Food intake; Body weight
Obesity has become a major health problem in the industrialized world during the past few decades [1,2]. The World Health Organization has estimated that ⬎1.6 billion adults (age ⱖ15 years) are overweight and ⱖ400 million are *Reprint requests: Ghassan S. Kassab, Ph.D., Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202. E-mail: [email protected]
considered obese [3]. Obesity increases the risk of diabetes, stroke, hypertension, heart disease, kidney disease, gallbladder disease, osteoarthritis, and depression [4,5]. Weight loss has been found to improve or resolve these co-morbidities [6 – 8]. Of the available therapeutic modalities, bariatric surgery has been found to be the most effective and durable treatment of morbid obesity. In response, interest has been increasing in the surgical treatment of morbid obesity. Bariatric surgery (e.g., Roux-en-Y gastric bypass, adjustable
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gastric banding, vertical sleeve gastrectomy [VSG]), by restrictive or malabsorptive methods, is the only current treatment capable of sustaining profound weight loss [6,9,10]. VSG has gained significant interest as a definitive bariatric operation in the past decade. It provides superior weight loss results, with an acceptable safety profile, at least in short-term follow-up studies, because follow-up data ⬎5 years are not yet available [11–13]. The sleeve is created by placing a vertical staple line and removing the remaining 85% of the stomach, to leave a long banana-like pouch. The VSG generates weight loss solely through a marked reduction of hunger and a reduced gastric capacity, but without malabsorption. Changes in the gastrointestinal hormonal levels have been proposed to contribute to the mechanism of weight reduction after bariatric surgery [14 –17]. The possible hormonal mechanisms involved in sustainable weight loss are still debated [14 –16,18]. Despite the efficacy, the current VSG procedures have several limitations, including the risk of staple line leaks and late complications, such as weight regain with gastric sleeve dilation. Moreover, longterm (⬎5 years) outcomes are still pending [12,19 –21]. In addition, the gastric sleeve is not reversible. To mimic the benefits of VSG without some of the shortcomings, we have proposed a VSG-like device termed the “gastric sleeve magnetic implant” (GSMI). The device uses permanent magnets to form the line of restriction, rather than surgical staples and gastrectomy, such as in the VSG procedure. The objective of the present study was to evaluate the feasibility of the reversible GSMI for weight loss in the Zucker fatty and Wistar rats. Methods Rats A total of 35 Zucker fatty rats, 14 –15 weeks old, and 12 healthy Wistar rats, 12–13 weeks old (Charles River Laboratories, Wilmington, MA) were used in the present study. Group 1 (18 Zucker fatty rats) underwent GSMI placement for a 6-week period and was killed at the end of the 6 weeks. Group 2 (17 Zucker fatty rats) served as the sham-operated controls for group 1. They underwent an identical surgical procedure, except without the actual implantation, and were also killed at the end of the 6 weeks. Group 3 (7 Wistar rats) underwent GSMI placement for a 6-week period but were allowed to recover for 4 weeks after implant removal. Group 4 (5 Wistar rats) was used as the sham-operated control for group 3. All animal experiments were performed in accordance with national and local ethical guidelines, including the Institute of Laboratory Animal Research guidelines, Public Health Service policy, the Animal Welfare Act, and an approved University of Indiana-Purdue University Indianapolis protocol regarding the use of animals in research.
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Surgical procedure All rats were maintained in individual cages with controlled temperature (21–23°C), humidity, and light (12 hours light and 12 hours dark), with free access to commercial standard rat chow and tap water. The food intake was recorded daily for 1 week. Each rat was weighed before each surgical procedure. Surgical implant After a 12-hour overnight fast, the rat was anesthetized with intraperitoneal ketamine (100 mg/kg) and xylazine (8 mg/kg). An abdominotomy (about 2 cm) was performed on the ventral midline. Gauze moistened with sterilized saline was placed around the incision. The stomach was then pulled out gently and placed on the gauze. A continuous 5-0 polypropylene suture was used to suture the front and back walls of the rumen (fibrotic portion of the stomach) together along the limiting ridge, a low fold of tissue that separates the rumen and corpus. The corpus (glandular portion) of the stomach was left intact. Additional interrupted stitches were used to reinforce the external wrap, as needed (Fig. 1). One disk magnet jacketed with a polyurethane sleeve (size 10 mm ⫻ 6 mm ⫻ 2 mm; Br 1500 Gauss) was then placed on the posterior surface of stomach to create a small stomach pouch and an outlet. Another disk magnet (size 10 mm ⫻ 4 mm ⫻ 2 mm; Br 1500 Gauss) with 4 standoff pins (length ⬃4 mm, about the thickness of the 2 walls of the stomach) was longitudinally placed on the anterior surface of the stomach along lesser curvature (Fig. 1). This created a diameter of the sleeve of about 5 mm (distance to the lesser curvature). Because the 2 magnets attracted each other, the pins or 2 staples (standard titanium staples) penetrated the gastric wall and locked into the back magnet, exterior to the stomach. The pins not only prevented overcompression of stomach, but they also prevented the magnets from migrating laterally along the surface of the stomach. The space between the 2 magnets contained lightly compressed gastric wall (the length of a pin was approximately the thickness of the “sandwiched” tissue; i.e., twice the wall thickness). For the sham-operated groups (groups 2 and 4), the rumen was also sutured, as described for the experimental group. Only the disk magnet with 4 standoff pins penetrating the anterior wall was sutured to the surface of the stomach. The stomach was then placed back into the abdomen, and the muscle and skin were closed. Terminal studies of Zucker rats The Zucker fatty rats (groups 1 and 2) were fasted overnight. The rats were killed by administration of an overdose of ketamine and xylazine. The stomach was excised immediately and fixed for later histologic evaluation.
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stomach was carefully removed, and the stomach was pulled back into the abdomen. The anterior disk magnet was left in the abdomen. For the sham-operated group (group 4), the stomach was only pulled out gently and then placed back into the abdomen. The Wistar rats were killed at 10 weeks— 4 weeks after implant removal. The surgical procedure was identical to that described for the Zucker fatty rats. Food intake and weight change After the first 12 hours of fasting after surgery, the Zucker fatty and Wistar healthy rats were given the same standard food chow and water. Food intake was measured daily for the first 2 weeks and then every 2 days for the remainder of the study. The rats’ body weight was measured weekly after surgery. The weight gain rate was defined as weight gain rate in percentages ⫽ [(body weight ⫺ initial weight)/initial weight] ⫻ 100%. Histologic evaluation At death, the gastric tissue immediately below the implant, as well as the tissue adjacent to the implant, for both the Zucker fatty and the Wistar rats was harvested and fixed with 10% formalin in phosphate buffer for at least 10 hours. The sample was then embedded in J-B4 resin and crosssectioned at 3 m thickness. The tissue samples were stained with hematoxylin and eosin and trichrome Masson and examined under a light microscope. Statistical analysis The results are presented as the mean ⫾ standard deviation, and the significance of differences between 2 groups was evaluated using 2-way analysis of variance. The results were considered statistically significant at P ⬍.05 (2-tailed). Fig. 1. Magnetic implantation in rat stomach. (A) Two magnetic clamp halves (1 anterior and 1 posterior) deployed on either side of stomach pouch. Pins between magnetic halves served to maintain distance to prevent stomach compression. (B) Sleeve diameter created by magnetic implants around 5 mm (distance to lesser curvature). Rumen wrapped with suture.
Implant removal Because the Zucker fatty rats are severely sick animals with hypercholesterolemia, hyperinsulinemia, hypertriglyceridemia, hyperlipidemia, and the metabolic syndrome and eventually develop serious cardiovascular diseases and other complications [22–26], they would have been too weak to undergo a second procedure for removal of the device. Thus, a group of normal Wistar rats was used to evaluate implant removal. Anesthesia, sterility, and preparation remained the same as described for implantation. An abdominotomy (about 2 cm) was performed on the ventral midline. The stomach was pulled out gently and placed on gauze. The disk magnet placed in the posterior surface of
Results We only considered the Zucker fatty rats that survived (n ⫽ 20) the surgical procedure without any postoperative complications. Of the 35 Zucker fatty rats, 15 were excluded from analysis because of different postoperative complications: 2 anesthetic deaths, 2 wound infections, 1 case of gastric bleeding, 2 with implant intragastric migration, and 8 with heart failure (substantial ascites and cardiac hypertrophy). All 12 Wistar rats that underwent surgical implantation and implant removal recovered successfully and survived until the termination date. The baseline mean body weight was comparable in the 2 groups of each type of rat before treatment. For the Zucker fatty rats, the mean body weight was 575.3 ⫾ 35.1 g in the experimental group and 551.5 ⫾ 28.4 g in the sham-operated group (P ⫽ .83). For the Wistar rats, the mean body weight was 421.7 ⫾ 55.2 g in the experimental and 420.2 ⫾ 44.5 g in the sham-operated rats (P ⫽ .98).
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The food intake was measured daily and summed for the week. Fig. 2A shows that the food intake was initially reduced in the first postoperative week and then recovered after 2 weeks in both the experimental and the sham groups for the Zucker fatty rats. The food intake was significantly lower in the experimental group than in the sham group throughout the 6-week period (P ⬍.05). The animal body weight was measured weekly after the surgical procedure. In line with the reduced food intake, the weight gain rate was reduced during the first weeks after surgery (Fig. 2B). Thereafter, the weight gain rate was significantly lower in the experimental group compared with that for the sham group (P ⬍.01). The change in food intake for the Wistar rats that underwent implant removal was similar to that of Zucker fatty rats (Fig. 3A). The food intake in the experimental group was significantly less than that for the sham-operated group during the 6-week period (P ⬍.05). The decrease in food intake in week 7 was not statistically significant for either group after implant removal. Subsequently, the significant decrease in food intake in the experimental group was sustained in weeks 8 –10 (P ⬍.05). Fig. 3B shows the weight gain rate for the experimental group was significantly decreased compared with that for the sham-operated group (P ⬍.05). Similarly, no difference in the weight gain rate was observed between the experimental and sham groups in week 7. In the subsequent 3 weeks, however, the
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Fig. 3. (A) Food intake and (B) weight gain rate in experimental and sham-operated Wistar rats for 10 weeks after implant surgery and implant removal. Arrow indicates implant removal at week 6. Food intake and weight gain rate significantly lower in experimental than in sham-operated rats at every week after surgery (P ⬍.05), except for seventh week owing to influence of surgery.
weight gain rate was still lower in the experimental group than that in the sham-operated group (P ⬍.05). We evaluated the stomach of the Zucker fatty rats at 6 weeks and of the Wistar rats at 10 weeks after surgical implantation and found no gross changes in the submucosa or mucosa, and no tissue ischemia or necrosis (Fig. 4). Typically, a fibrotic capsule had formed around the magnet
Fig. 2. (A) Food intake and (B) weight gain rate in experimental and sham-operated Zucker fatty rats for 6 weeks after implant surgery. Food intake and weight gain rate were significant lower in experimental than in sham rats at each week after surgery (P ⬍.05).
Fig. 4. Gastric mucosa after removal of implant showing normal tissue without inflammation, adhesion, or necrosis.
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Discussion
Fig. 5. (A) Removal of posterior magnet after incision of capsule that formed around magnet at end of 6 weeks of surgical implantation in Wistar rats. (B) Pseudocapsule after implant removal showing normal tissue without inflammation or necrosis.
within a few days. This capsule could be easily excised to remove the magnet (Fig. 5). Examination of the JB-4 resin sections under light microscopy showed that the surface columnar cells and gastric glands were undamaged in both the Zucker fatty and the Wistar sham-operated rats (Fig. 6A,B). The ratio of stroma to glands was normal. The implant caused mild vascular ectasia with infiltration of the inflammatory cells (lymphocytes and fibroblast) in the submucosa, muscular layer, and serosa. For the Zucker fatty and Wistar experimental groups, the histologic examination found that the basic architecture of the columnar epithelium after magnetic implant was unaltered (Fig. 6C,D). The gastric glands exhibited mild fibrosis in the lamina propria close to the mucosa with the appearance of scattered inflammatory cells (lymphocytes and fibroblasts). The density of the connective tissue in the mucosa and serosa region had increased. Small hyperplasia of the arteries in the muscular layer was seen with evident venous dilation. Granulation tissue was also present in the serosa region.
Bariatric surgery is the most effective treatment of severe obesity, because it allows sustained weight loss and improves most of the co-morbidities associated with the disease [6]. VSG has been used for the surgical treatment of morbid obesity in humans [14,27], and the results have been very promising. In the present study, a VSG-like device, the GSMI, was used to reduce the gastric capacity and hence lead to diminished food intake. This was accomplished without the need for gastrectomy and could be easily dismantled. It is well known that significant differences exist in the anatomy of the stomach between humans and rats. The rat stomach has a rumen (thin-walled, nonglandular section that forms two fifths of the stomach) that is directly connected to the esophagus. It serves as a holding chamber for food and perhaps a pouch for the esophagus, instead of a true stomach. In theory, suturing off the rumen might diminish the gastric capacity and result in a reduction in food intake. It has been conformed that a prosthetic external wrap of the folded stomach produces weight loss in humans [28]. Nevertheless, in the present study, to best approximate the anatomy of the human stomach and minimize the possible influence produced by the rumen, we sutured off this anatomic structure in both the experimental and the shamoperated groups. We found significant differences between the treated rats and sham-operated controls with regard to both food intake and body weight. The food intake was significantly lower for the experimental group compared with the sham-operated group during the 6 weeks of implant (Fig. 3A). On average, the food intake was reduced by 18.2%/wk compared with the sham-operated rats 1 week after surgery. Because the Zucker fatty rats at 15 weeks of age are still growing, we did not expect to observe a decrease in the absolute body weight but rather a decrease in the weight gain. After bariatric surgery with GSMI placement, the Zucker fatty rat exhibited a significant decrease in the weight gain rate compared with the sham-operated group (Fig. 3B). On average, the weight gain rate was decreased by 15.8% during the 6-week period (2.9%/wk). Recently, Pereferrer et al. [29] reported that sleeve gastrectomy had a slight effect on food intake and body weight in Zucker fatty rats. When corrected for age, the excess weight loss in these rats was reported as 7.3% after 3 weeks of sleeve gastrectomy. de Bona Castelan et al. [30] studied sleeve gastrectomy in Wistar rats and found that both the sleeve gastrectomy and the control group gained weight throughout the 7 postoperative weeks. In the VSG group, however, this weight gain was significantly lower than that in the control group. Our data on the GSMI suggest similarly positive results in the reductions in food intake and weight gain rate. Unlike the VSG, the GSMI can be easily dismantled. The effect of implant removal was evaluated in Wistar rats in the present study. In general, the food intake and body weight
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Fig. 6. Histologic images of gastric wall in response to magnetic implant in (A,B) sham-operated and (C,D) experimental groups for both Zucker fatty and Wistar rats. Trichrome Masson staining, original magnification ⫻400. (A) Gastric mucosa from sham-operated Zucker fatty group. No histological damage seen in surface epithelium, gastric pits, or gastric glands. (B) Gastric glands, mucosa, and submucosa from sham-operated Wistar group. Implant caused mild vascular ectasia with infiltration of inflammatory cells (lymphocytes and fibroblasts) in submucosa, muscular layer, and serosa. Gastric glands (Bottom right) were normal. (C) Gastric mucosa from experimental Zucker fatty group. No histologic damage seen in simple columnar epithelium or gastric glands. Blood vessels in mucosa layer revealed mild vascular ectasia. (D) Gastric glands, mucosa, and submucosa from experimental Wistar group. Gastric glands near mucosa exhibited mild fibrosis with appearance of scattered inflammatory cells (Top right). Moderate fibrosis and venous dilation were also present (Left). Small arteries with vascular ectasia were seen in mucosa layer (Middle).
decreased in the first postoperative week owing to the surgical trauma induced by the surgical implant and removal. During the 6 weeks after surgical implant, the food intake and weight gain rate were significantly lower in the experimental group than in the sham-operated group (Fig. 3). On average, the weight gain rate decreased by 14.6% during the 6-week period. The decrease in food intake and weight gain rate was maintained in the experimental group but not in the sham group at 4 weeks after implant removal. The decrease in the weight gain rate in the experimental group was maintained at 12.9% during the 10-week period. Evidence is growing that bariatric surgery can influence the systems that regulate appetite and satiety [14,15,31,32]. Because the present experiments focused on the feasibility of the surgical implant and implant removal, we could not provide a mechanistic explanation for the sustainability of the weight gain rate after implant removal. Future follow-up regarding long-term weight loss maintenance and a prolonged influence on metabolism is necessary. The Zucker fatty rat was selected as the experimental model because it is a spontaneous genetic model of obesity that exhibits hyperphagia, hyperinsulinemia, and hyperlipidemia [22–24], which better replicates most of the features observed with human obesity. However, we found that the
Zucker fatty rats had high morbidity and mortality rates (35%) in the present study. It has been reported that Zucker fatty rats die rapidly after 9 months of follow-up, with a mortality rate of 64% in the absence of any surgical intervention. The shortened lifespan mainly results from the development of severe renal failure [25]. Grosfeld et al. [33] found that Zucker fatty rats undergoing jejunoileal bypass were more fragile and prone to die, with a 33% mortality rate compared with normal rats. A recent study by Marsh et al. [26] using the Zucker fatty and Zucker diabetic fatty rat models showed unexpectedly high mortality rates shortly after the creation of aortocaval fistula. The deaths were thought to relate to a high incidence of renal and cardiac dysfunction. Our results, coupled with these cited studies, suggest that the Zucker fatty rat is not an appropriate model for a surgical procedure or a long-term study owing to the renal and cardiovascular morbidity and mortality. One common complication seen in the VSG is a leak at the staple lines of the stomach, resulting in infection [12]. No leakage and/or laceration, leading to intraperitoneal infection, caused by the pins of the magnet penetrating both walls of the stomach was observed in any Zucker fatty or Wistar rats in our study. It is plausible that because of the contraction of the gastric smooth muscle, the small incision
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on the stomach wall by the pins (staple with 0.4 mm diameter) closed after surgical implantation, and thus, no leak at the pin sites was observed. We found only 3 cases of postoperative complications directly caused by the device. One Zucker fatty rat died of gastric bleeding 24 hours after surgical implantation because of inadvertent puncture of a large artery around the area of the lesser curvature by the pins. More careful inspection before deploying the device can prevent this incident. Two rats with intragastric migration survived and had no obvious symptoms until death. The pathologic necropsy findings showed that the 2 magnets were closed together end-to-end, resulting from a device imbalance. The gastric wall between the 2 magnets was overcompressed, and 1 end of the 2 magnets had gradually migrated into the stomach. This problem arose from the size of the magnetic plates for the rat studies because they can easily tilt. The device for large animal studies is much more stable. To determine the influence of the magnetic implant on the stomach wall, we evaluated the histologic changes in the gastric wall. The histologic findings in the experimental and sham groups for both the Zucker fatty and the Wistar rats were similar (Fig. 6). The most prominent and persistent change from the mucosa to the serosa layer induced by the magnetic implant was a scattered inflammatory mononuclear cell infiltration and mild fibrosis and hyperplasia of blood vessels, as expected for any implant. No evidence was seen of hemorrhage, necrosis, or thrombosis in the gastric wall proximally or distally to the magnetic implant. Our histologic findings have indicated that the GSMI implant maintains the histologic architecture of the stomach in both fatty Zucker and Wistar rats.
Conclusion The results of our study have shown that the GSMI significantly decreases food intake and body weight gain in Zucker fatty and healthy Wistar rats. Furthermore, the reduction in the weight gain rate was sustained for 4 weeks after implant removal. Our results have verified that the GSMI device is feasible and can be removed easily after implantation in the rat model. We have no doubt that a reversible, cost-effective implantable device that maintains the normal anatomic configuration of the overall stomach with effective weight loss would be of significant interest to both patients and surgeons in the fight against obesity. Additional evaluation of the long-term safety and efficacy of the GSMI in larger animals is needed.
Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article.
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