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Delivery of Allogeneic Adipose Stem Cells in Polyethylene Glycol-Fibrin Hydrogels as an Adjunct to Meshed Autografts After Sharp Debridement of Deep Partial Thickness Burns.

ABSTRACT: Harvesting of autografts results in donor site morbidities and is limited in scenarios such as large total body surface area burns. In these instances, coverage is increased by meshing grafts at the expense of delayed biologic closure. Moreover, graft meshing increases the likelihood of contraction and hypertrophic scarring, limits range of motion, and worsens cosmesis. Many tissue engineering technologies have touted the promise of adipose-derived stem cells (ASCs) for burn wounds. The primary objective of the current study was to determine feasibility and efficacy of in situ ASC delivery via PEGylated fibrin (FPEG) hydrogels as adjuncts to meshed split thickness skin grafts in a porcine model. Deep partial thickness burns were created on the dorsum of anesthetized Yorkshire pigs, and subsequently debrided on post-burn day 4. After debridement, wounds were treated with: split thickness skin grafts (STSG); meshed STSG (mSTSG); and mSTSG + FPEG with increasing doses of ASCs. We show that FPEG hydrogels can be delivered in situ to prevent the contraction seen after meshing of STSG. Moreover, ASCs delivered in FPEG dose-dependently increase blood vessel size which significantly correlates with CD31 protein levels. The current study reports a dual-action adjunct therapy to autografting administered in situ, wherein FPEG acts as both scaffolding to prevent contraction, and as a delivery vehicle for ASCs to accelerate angiogenesis. This strategy may be used to incorporate other biologics for generating tissue engineered products aimed at improving wound healing and minimizing donor sites or scarring. Stem Cells Translational Medicine 2018;7:360-372.

SUBMITTER: Burmeister DM

PROVIDER: S-EPMC5866942 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Polyethylene glycol (PEG) is widely used in industry and medicine. Anti-PEG antibodies have been developed for characterizing PEGylated drugs and other applications. However, the underlying mechanism for specific PEG binding has not been elucidated. METHODS:The Fab of two cognate anti-PEG antibodies 3.3 and 2B5 were each crystallized in complex with PEG, and their structures were determined by X-ray diffraction. The PEG-Fab interactions in these two crystals were analyzed and compared with those in a PEG-containing crystal of an unrelated anti-hemagglutinin 32D6-Fab. The PEG-binding stoichiometry was examined by using analytical ultracentrifuge (AUC). RESULTS:A common PEG-binding mode to 3.3 and 2B5 is seen with an S-shaped core PEG fragment bound to two dyad-related Fab molecules. A nearby satellite binding site may accommodate parts of a longer PEG molecule. The core PEG fragment mainly interacts with the heavy-chain residues D31, W33, L102, Y103 and Y104, making extensive contacts with the aromatic side chains. At the center of each half-circle of the S-shaped PEG, a water molecule makes alternating hydrogen bonds to the ether oxygen atoms, in a similar configuration to that of a crown ether-bound lysine. Each satellite fragment is clamped between two arginine residues, R52 from the heavy chain and R29 from the light chain, and also interacts with several aromatic side chains. In contrast, the non-specifically bound PEG fragments in the 32D6-Fab crystal are located in the elbow region or at lattice contacts. The AUC data suggest that 3.3-Fab exists as a monomer in PEG-free solution but forms a dimer in the presence of PEG-550-MME, which is about the size of the S-shaped core PEG fragment. CONCLUSIONS:The differing amino acids in 3.3 and 2B5 are not involved in PEG binding but engaged in dimer formation. In particular, the light-chain residue K53 of 2B5-Fab makes significant contacts with the other Fab in a dimer, whereas the corresponding N53 of 3.3-Fab does not. This difference in the protein-protein interaction between two Fab molecules in a dimer may explain the temperature dependence of 2B5 in PEG binding, as well as its inhibition by crown ether.

Project description:Background and aimsGI tract perforations and anastomotic dehiscence are increasingly effectively being repaired endoscopically; however, well-known and long-held surgical principles must still be honored. One important principle is that significant extraluminal contamination must be washed out, debrided, and drained in conjunction with repair of the defect if the wound is to effectively heal and resolve. Here we describe the use of endoscopic washout and debridement of extraluminal contamination at the time of luminal defect closure in a 7-patient series at our institution, with video demonstration of 2 patients in the series.MethodsWe reviewed a series of 7 patients at our institution and provide a video demonstration of the described technique in 2 patients. A 50-year-old man with decompensated liver cirrhosis presented with a large distal esophageal disruption secondary to a severe Minnesota tube injury. Extensive thoracic and mediastinal contamination of solid and liquid debris was removed and washed out endoscopically, followed by esophageal defect repair. Closure of the defect with overlapping, fully covered, esophageal stents sutured in place was successful after attempts at repairing the primary disruption with suturing alone failed. A 49-year-old man with multiple endocrine neoplasia type 1 and multiple prior surgeries presented with an acute abdomen and sepsis secondary to a fully perforated duodenal ulcer. Extensive endoscopic washout and lavage of the purulent liquid and semiliquid debris covering the liver, stomach, and adjacent structures was performed, followed by closure of the perforation by endoscopic suturing. A percutaneous pigtailed drainage catheter was placed in the extraluminal cavity to facilitate postoperative drainage, followed by placement of a PEG with jejunal extension for enteric exclusion and nutrition.ResultsThe results for all 7 patients were reviewed. The overall rate of technical success, defined as effective repair of the luminal defect and drainage of extraluminal contamination, was 100%. The overall rate of clinical success, defined as clinical recovery and return to the patient's previous state of health, was 86% because 1 patient died because of severe concomitant disease. The length of time from the described procedure to hospital discharge ranged from 8 to 52 days (mean, 27 days).ConclusionEndoscopic washout and debridement can effectively and immediately address extraluminal contamination at the time of endoscopic luminal defect repair in appropriately selected patients. Therefore, it may represent a valuable option to address this clinical situation when a more conventional surgical approach is problematic. A more structured study should be considered for the development and validation of this approach.

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Delivery of Allogeneic Adipose Stem Cells in Polyethylene Glycol-Fibrin Hydrogels as an Adjunct to Meshed Autografts After Sharp Debridement of Deep Partial Thickness Burns.

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