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A Novel Therapy for Short Bowel Syndrome: Bowel Lengthening Device
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Farokh R. Demehri, MD, and Daniel H. Teitelbaum, MD

 

Short bowel syndrome (SBS) is a challenging disease that can have a life-long impact on patient health and quality of life. There is a high rate of mortality associated with SBS. Patients with SBS often require parenteral nutrition (PN) to maintain their nutritional status, and while PN can be life-saving, many infants as well as adults suffer from a number of PN-related complications. For patients who are unable to wean from PN, current treatment strategies include surgical lengthening of the small bowel, administration of growth hormones, and small bowel transplantation—all with widely variable results.

 

Mechanotransduction, or the conversion of mechanical forces into cellular signals, is an emerging area of research that may provide a novel treatment for SBS. With mechanotransduction, tissue growth is induced by applying mechanical force to tissues. These forces drive chemical cellular signals that stimulate the growth of cells and whole tissues. This principle has been described for well over a century. It has been applied in using a mechanical ratcheting device to help a shorter leg grow longer.

 

“Distraction-induced enterogenesis” is a term we use to describe the process by which the intestine lengthens with application of intraluminal linear forces (mechanical force applied lengthwise within the intestine). Through this process, the bowel not only lengthens, but the lengthened bowel demonstrates normal function as well. This has now been demonstrated in a number of animal models, including rats, mice, and pigs. A number of studies demonstrate that the lengthened intestine absorbs nutrients and performs peristalsis (to aid the passage of contents through the intestine) normally.

 

Our laboratory has spent the last decade developing a series of novel devices that can lead to such intestinal growth. This short article describes some of the goals for this process, and the challenges that must be addressed before it can be successful on a clinical basis.

 

Goals 

Our laboratory has shown that patients with less than 10 percent of their normal intestinal length have a very poor chance of weaning from PN. We consider these patients good candidates for enterogenesis. Ideally, in addition to successfully creating enterogenesis in the patient, the device we develop will be implantable with minimal surgical intervention (e.g., endoscopic placement); safely attach to the intestine (couple to the inner lumen of the bowel); and uncouple from the bowel wall for easy removal.

 

We have used a young adult pig model for most of the work we’ve done in our laboratory. This model has allowed us to scale the size of the devices we’ve developed to the size that would be used in children or adults. Figure 1 shows the concept of one device implanted in a pig. Using a hydraulic device that we had implanted in the pig’s small bowel, we were able to achieve a 2- to 2.7-fold increase in intestinal length over a two-week period.

 

How does this hydraulic device work? We inject saline into the device through a tube brought outside of the pig. This fluid drives the hydraulic device to expand—much like the opening up of a telescope that has multiple tubes. We have been successful in elongating the bowel with this device. However, to date the work has typically involved at least two surgical procedures: one to implant the device and another to remove it. It is our goal to minimize surgery, as additional surgeries increase risk of surgical adhesions and infection.

 

 
 

Figure 1. Distraction-induced enterogenesis.

In this experimental model,

a curved hydraulic pump was implanted

into an isolated segment of small intestine.

Gradual hydraulic device expansion

achieved up to 2.7-fold

lengthening over two weeks.

   
   
 

Figure 2. Fully endoluminal distraction-induced

enterogenesis device. In this current model,

two balloons are used to anchor the device to the

inside of the intestine. This device can be implanted,

extended, and removed via a stoma, allowing

intestinal growth without additional operations.

   
   
 

The fully endoluminal distraction-induced

enterogenesis device implanted

in a pig’s intestine.

Current Work  

Figure 1. Distraction-induced enterogenesis. In this experimental model, a curved hydraulic pump was implanted into an isolated segment of small intestine. Gradual hydraulic device expansion achieved up to 2.7-fold lengthening over two weeks.
 
With the support of the Hartwell Foundation, the National Institutes of Health (NIH), and the Food and Drug Administration (FDA), we are working to address the shortcomings of our previous work. Figure 2 shows the design of our current bowel-lengthening device. This new design allows for endoscopic or radiologic placement of the device, rather than surgical placement. The two balloons can be inflated. The friction the inflated balloons create provides attachment to the inner lumen of the bowel. The device can then be mechanically extended between the two balloons using a hydraulic concept similar to the one described above. To remove it, the balloons are deflated and the device is pulled out through an intestinal stoma.

 

While this device offers many improvements compared to our previous generation of devices, we still face several challenges. Our first is the need for a better and safer way to couple the device to the inner surface of the intestine. The second challenge is to improve our ability to measure how much force we are placing on the intestine during the process of enterogenesis. Too little force will fail to drive intestinal growth, while too great of a force will lead to intestinal perforation.

 

Future Directions and Challenges 

Figure 2. Above: Fully endoluminal distraction-induced enterogenesis device. In this current model, two balloons are used to anchor the device to the inside of the intestine. This device can be implanted, extended, and removed via a stoma, allowing intestinal growth without additional operations.
Right: The fully endoluminal distraction-induced enterogenesis device implanted in a pig’s intestine.
 
Our laboratory is now preparing a next generation device. This device will ideally be ready for a clinical trial in the next few years. However, many internal and external challenges exist. This includes refinement of the present device with improved safety features and modifications for straightforward clinical utility. These refinements appear readily achievable.

 

External challenges will include clinical testing of this device for efficacy and safety. An even greater external challenge will be an economic one. Bringing such a device to market will not be easy. One of the greatest challenges we face is the fact that SBS is a rare disease. Attracting a company to partner with in the clinical development of this device has been quite challenging.

 

References 

Bianchi A. Longitudinal intestinal lengthening and tailoring: results in 20 children. J R Soc Med 1997;90:429-32.
Codivilla A. On the means of lengthening, in the lower limbs, the muscles and tissues which are shortened through deformity. 1904. Clin Orthop Relat Res 1994:4-9.
Hess RA, Welch KB, Brown PI, Teitelbaum DH. Survival outcomes of pediatric intestinal failure patients: analysis of factors contributing to improved survival over the past two decades. J Surg Res 2011;170:27-31.
Hoffman BD, Grashoff C, Schwartz MA. Dynamic molecular processes mediate cellular mechanotransduction. Nature 2011;475:316-23.
Kim HB, Fauza D, Garza J, Oh JT, Nurko S, Jaksic T. Serial transverse enteroplasty (STEP): a novel bowel lengthening procedure. J Pediatr Surg 2003;38:425-9.
Koga H, Sun X, Yang H, Nose K, Somara S, Bitar KN, Owyang C, Okawada M, Teitelbaum DH. Distraction-induced intestinal enterogenesis: preservation of intestinal function and lengthening after reimplantation into normal jejunum. Ann Surg 2012;255:302-10.
Nishisho T, Yukata K, Matsui Y, Matsuura T, Higashino K, Suganuma K, Nikawa T, Yasui N. Angiogenesis and myogenesis in mouse tibialis anterior muscles during distraction osteogenesis: VEGF, its receptors, and myogenin genes expression. J Orthop Res 2012.
Okawada M, Maria HM, Teitelbaum DH. Distraction induced enterogenesis: a unique mouse model using polyethylene glycol. J Surg Res 2011;170:41-7.
O’Keefe SJ, Buchman AL, Fishbein TM, Jeejeebhoy KN, Jeppesen PB, Shaffer J. Short bowel syndrome and intestinal failure: consensus definitions and overview. Clin Gastroenterol Hepatol 2006;4:6-10.
Park J, Puapong DP, Wu BM, Atkinson JB, Dunn JC. Enterogenesis by mechanical lengthening: morphology and function of the lengthened small intestine. J Pediatr Surg 2004;39:1823-7.
Peretti N, Loras-Duclaux I, Kassai B, Restier-Miron L, Guimber D, Gottrand F, Coopman S, Michaud L, Marinier E, Yantren H, Michalski MC, Aubert F, Mercier C, Pelosse M, Lopez M, Chatelain P, Lachaux A. Growth hormone to improve short bowel syndrome intestinal autonomy: a pediatric randomized open-label clinical trial. JPEN J Parenter Enteral Nutr 2011;35:723-31.
Spencer A, Safran J, Neeaga A, Brown P, Btaiche I, Teitelbaum D. Mortality and Outcomes of Pediatric Short Bowel Syndrome: Redefining Predictors of Success. Annals of Surgery 2005;242:1-10.
Stark R, Zupekan T, Bondada S, Dunn JC. Restoration of mechanically lengthened jejunum into intestinal continuity in rats. J Pediatr Surg 2011;46:2321-6. 

 

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This website is an educational resource. It is not intended to provide medical advice or recommend a course of treatment. You should discuss all issues, ideas, suggestions, etc. with your clinician prior to use. Clinicians in a relevant field have reviewed the medical information; however, the Oley Foundation does not guarantee the accuracy of the information presented, and is not liable if information is incorrect or incomplete. If you have questions please contact Oley staff.

 

Updated in 2015 with a generous grant from Shire, Inc. 

 

This website was updated in 2015 with a generous grant from Shire, Inc. This website is an educational resource. It is not intended to provide medical advice or recommend a course of treatment. You should discuss all issues, ideas, suggestions, etc. with your clinician prior to use. Clinicians in a relevant field have reviewed the medical information; however, the Oley Foundation does not guarantee the accuracy of the information presented, and is not liable if information is incorrect or incomplete. If you have questions please contact Oley staff.
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