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Esophageal Tissue Engineering

Esophageal adenocarcinoma is increasing at a faster rate than any other cancer in the United States. Treatment options include a variety of techniques to resect the affected tissue but these strategies have had limited success and invariably have high complication and mortality rates.

To investigate the use of biologic scaffold materials as a regenerative medicine approach to induce esophageal repair after partial or total esophagectomy and/or mucosectomy.

Extracellular matrix (ECM)-based biomaterials have shown promise for esophageal reconstruction. In early pre-clinical studies ECM scaffolds were used to repair partial and full thickness esophageal defects encompassing various portions of the total esophageal circumference. This initial study showed well organized, fully re-epithelialized site-specific tissue that was contiguous with the native esophagus. However, full circumferential defects healed with stricture within 19 days after surgery [1].

Subsequent studies were designed to show that a critically sized, full circumferential esophageal defect could be repaired with minimal stricture formation if adjacent autologous muscle tissue was placed in direct apposition to the ECM scaffold at the time of surgery [2]. The ECM scaffolds provide an ideal substrate for epithelial layer development and this, combined with the presence of skeletal muscle cells, may have facilitated the re-epithelialization necessary to prevent or minimize tissue contracture [3]. The study also showed spontaneous motility of the muscle within the remodeled section via esophograms and endoscopy, although the motility did not appear to be synchronous with the native esophagus. Immunolabeling at the site of ECM-facilitated remodeling showed mature and regenerating nerves within the newly formed muscle tissue [4]. The mechanical behavior of the remodeled tissue—although the biologic scaffold was much stiffer and stronger than the native tissue at the time of surgery—approached the mechanical behavior of the normal esophagus by 3 months post-implantation [2].

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Figure 1: Tubular ECM scaffold used to repair esophageal defects [2]

Figure 2: Depiction of surgical procedure used to treat human patients with diseased esophageal muscosa. The mucosal lining is removed and replaced with a tubular ECM scaffold, which leads to restoration of normal

To facilitate rapid clinical translation of an ECM scaffold approach to esophagus reconstruction, a study was designed to specifically evaluate the efficacy of an ECM scaffold in a surgical procedure that is currently performed, and accepted, namely the “gastric pull-up” procedure [5]. In an animal model, transections were made in the cervical esophagus and at the gastroesophageal junction and a few centimeters of mucosa were also resected. The 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. The remodeling of the ECM reinforced anastomoses was compared to an experimental control in which the endomucosal 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 resulted in less stenosis and less contracture of the cervical and distal esophagus compared to the control. 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 tissues 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.

Figure 3: Diagnostic biopsy (top row), postoperative biopsy (second row). The diagnostic biopsies all show adenocarcinoma. The postoperative biopsies show replacement of the ECM scaffold with mature, differentiated squamous epithelium. Scale bars represent 100 mm.

Naturally, in order to develop better regenerative medicine therapies for esophageal reconstruction, a more thorough understanding of esophageal disease progression and the mechanisms by which bioscaffolds mitigate the default tissue response to injury is required. The Badylak laboratory is currently working on these two separate but related questions: Specifically, we aim to determine the mechanism by which normal, inflammatory, and cancerous ECM dynamically, and reciprocally, instructs the behavior of esophageal cells and supporting cells (e.g. immune cells) through physical and biochemical cues. The Badylak laboratory is uniquely equipped to conduct this study for its pioneering work in decellularization of mammalian tissues and development of organ-specific hydrogels [8,9]. We are currently working to develop the first hydrogel from inflammatory and cancerous ECM. Furthermore, we aim to temporally resolve the microenvironment-specific tissue-remodeling response sequence after biologic scaffold placement in a rat model of esophageal adenocarcinoma. The findings of this work will improve regenerative medicine strategies for patients with Barrett’s and mucosal adenocarcinoma, and identify biomarkers for clinical surveillance in this increasingly devastating form of cancer.

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. 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
  5. 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
  6. 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
  7. Badylak SF, Hoppo T, Nieponice A, Gilbert TW, Davison JM, Jobe BA. Esophageal preservation in five male patients after endoscopic inner-layer circumferential resection in the setting of superficial cancer: a regenerative medicine approach with a biologic scaffold. Tissue Eng Part A. 2011;17(11-12): p. 1643- 50. PMID: 21306292
  8. Wolf MT, Daly KA, Brennan-Pierce EP, Johnson SA, Carruthers CA, D'Amore A, Nagarkar SP, Velankar SS, Badylak SF. A hydrogel derived from decellularized dermal extracellular matrix. Biomaterials. 2012 Oct;33(29):7028-38. doi: 10.1016/j.biomaterials.2012.06.051. Epub 2012 Jul 11. PMID: 22789723
  9. Medberry CJ, Crapo PM, Siu BF, Carruthers CA, Wolf MT, Nagarkar SP, Agrawal V, Jones KE, Kelly J, Johnson SA, Velankar SS, Watkins SC, Modo M, Badylak SF. Hydrogels derived from central nervous system extracellular matrix. Biomaterials. 2013 Jan;34(4):1033-40. doi: 10.1016/j.biomaterials.2012.10.062. Epub 2012 Nov 16. PMID: 23158935

 

 

Updated 20-Mar-2014