The Badylak laboratory has investigated the use of biologic scaffold as a regenerative medicine approach to esophageal reconstruction.  Esophageal cancer is increasing at a rate faster than any other type of cancer in North America and the only treatment is esophagectomy; a procedure that has high morbidity. Biologic scaffold materials, such as extracellular matrix (ECM) derived from various tissues, have shown promise for esophageal reconstruction.  In a canine model, SIS-ECM and porcine urinary bladder submucosa (UBS) have been evaluated for reconstruction of the esophagus after surgical creation of a full thickness defect in the cervical esophagus measuring 5 cm in length and encompassing 40-50% of the circumference or 100% of the circumference1. In the partial circumferential defects, the remodeling response resulted in well organized, site specific esophageal tissue that was fully epithelialized and contiguous with normal esophageal tissue by 50 days after surgery.  However, the full circumferential defects healed with stricture within 35 days after surgery.

In a subsequent study that used an ECM composed of the basement membrane and tunica propria of the porcine urinary bladder (UBM), it was shown that critically sized, full circumferential defects could be repaired with minimal stricture formation if adjacent autologous smooth muscle tissue was placed in direct apposition to the ECM scaffold at the time of surgery 2 (Figure 1).  The maintenance of the basement membrane on UBM provides an ideal substrate for epithelial layer development, and this, combined with the presence of skeletal muscle cells, may have facilitated the epithelialization necessary to prevent or minimize tissue contracture 3.  Spontaneous motility of the muscle within the remodeled section was shown by esophograms and endoscopy, although the motility did not appear to be synchronous with the native esophagus.  Immunohistochemical staining of the site of UBM-ECM remodeling showed the presence of mature and regenerating nerves within the newly formed muscle tissue 4.  The mechanical behavior of the graft was also evaluated, and it was shown that while the biologic scaffold material was much stiffer and stronger than the native tissue at the time of surgery, the remodeled tissue approached the mechanical behavior of the normal esophagus by 3 months after implantation 2. 

Since direct clinical translation of an ECM scaffold approach to esophagus reconstruction is likely to face skepticism, a pre-clinical study was performed to evaluate the efficacy of an ECM scaffold in a surgical procedure that is currently performed, namely the “gastric pull-up” procedure 5.  In a canine model, transections were made in the cervical esophagus and at the gastroesophageal junction and a few centimeters of mucosa were also resected.  The UBM-ECM was placed at the site of the endomucosal resection to reinforce the anastomosis.  The shape of the device was customized to the shape of the anatomy (i.e., tube for cervical, funnel shape for GE junction) in each location to reduce the anastomotic tension and disruption of blood supply (Figure 2).  The remodeling of the ECM reinforced anastomoses was compared to an experimental control, in which the endomucosa resection was performed at the time of anastomosis, and a clinical control, in which the mucosa was left intact.  After two months, the presence of UBM-ECM led to less stenosis and less contracture of the cervical and distal esophagus compared to control (Figure 3).  Furthermore, the site of ECM remodeling showed restoration of a more mature epithelium and regeneration of islands of muscle that bridged the gap between the native muscle tissue on either side of the surgical transection.  This study suggests that the use of an ECM scaffold during the gastric pull-up surgery may substantially decrease the rate of complications (i.e., stricture, leaks) associated with this procedure.  This work has formed the basis of a clinical trial that is currently in the planning stages.

Recently, the use UBM-ECM has been extended to pre-clinical a model of aggressive endoscopic endomucosal resection such as that proposed for treatment of Barrett’s disease 6.  A full-circumferential endomucosal resection of the cervical was performed endoscopically for a length of over a 5 cm (Figure 4).  A tubular UBM-ECM scaffold was then placed under endoscopic guidance and secure with a biodegradable tissue adhesive.  After two month, the injury treated with UBM-ECM was completely covered with a submucosal layer and stratified epithelium and there was less stenosis compared to controls without ECM treatment (Figure 5).  The use of an ECM scaffold may allow for more aggressive endomucosal resection of Barrett’s disease while reducing the frequency and severity of stricture.  We are excited to be extending this work to more aggressive EMR in collaboration with Dr. Blair Jobe.

References:

1. Badylak S, Meurling S, Chen M, Spievack A, Simmons-Byrd A. Resorbable bioscaffold for esophageal repair in a dog model. J Pediatr Surg. 2000 Jul;35(7):1097-1103. PMID: 10917304
2. Badylak SF, Vorp DA, Spievack AR, Simmons-Byrd A, Hanke J, Freytes DO, Thapa A, Gilbert TW, Nieponice A. Esophageal reconstruction with ECM and muscle tissue in a dog model. J Surg Res. 2005 Sep;128(1):87-97. PMID: 15922361
3. Brown B, Lindberg K, Reing J, Stolz DB, Badylak SF. The basement membrane component of biologic scaffolds derived from extracellular matrix. Tissue Eng. 2006 Mar;12(3):519-526. PMID: 16579685
4. Agrawal V, Brown BN, Beattie AJ, Gilbert TW, Badylak SF. Evidence of innervation following extracellular matrix scaffold mediated tissue remodeling. J Tissue Eng Regen Med. 2009 Dec;3(8):590-600. PMID: 19701935
5. Nieponice A, Gilbert TW, Badylak SF. Reinforcement of esophageal anastomoses with an extracellular matrix scaffold in a canine model. Ann Thorac Surg. 2006 Dec;82(6):2050-2058. PMID: 17126109
6. Nieponice A, McGrath K, Qureshi I, Beckman EJ, Luketich JD, Gilbert TW, Badylak SF. An extracellular matrix scaffold for esophageal stricture prevention after circumferential EMR. Gastrointest Endosc. 2008;doi:10.1016/j.gie.2008.04.022. PMID: 18657808