title: Growth factor release by vesicular phospholipid gels: in-vitro results and application for rotator cuff repair in a rat model.
abstract: BACKGROUND
  Biological augmentation of rotator cuff repair is of growing interest to improve biomechanical properties and prevent re-tearing. But intraoperative single shot growth factor application appears not sufficient to provide healing support in the physiologic growth factor expression peaks. The purpose of this study was to establish a sustained release of granulocyte-colony stimulating factor (G-CSF) from injectable vesicular phospholipid gels (VPGs) in vitro and to examine biocompatibility and influence on histology and biomechanical behavior of G-CSF loaded VPGs in a chronic supraspinatus tear rat model.
  
  
  METHODS
  G-CSF loaded VPGs were produced by dual asymmetric centrifugation. In vitro the integrity, stability and release rate were analyzed. In vivo supraspinatus tendons of 60 rats were detached and after 3 weeks a transosseous refixation with G-CSF loaded VPGs augmentation (n = 15; control, placebo, 1 and 10 μg G-CSF/d) was performed. 6 weeks postoperatively the healing site was analyzed histologically (n = 9; H&E by modified MOVIN score/Collagen I/III) and biomechanically (n = 6).
  
  
  RESULTS
  In vitro testing revealed stable proteins after centrifugation and a continuous G-CSF release of up to 4 weeks. Placebo VPGs showed histologically no negative side effects on the healing process. Histologically in vivo testing demonstrated significant advantages for G-CSF 1 μg/d but not for G-CSF 10 μg/d in Collagen III content (p = 0.035) and a higher Collagen I/III ratio compared to the other groups. Biomechanically G-CSF 1 μg/d revealed a significant higher load to failure ratio (p = 0.020) compared to control but no significant differences in stiffness.
  
  
  CONCLUSIONS
  By use of VPGs a continuous growth factor release could be obtained in vitro. The in vivo results demonstrate an improvement of immunohistology and biomechanical properties with a low dose G-CSF application via VPG. The VPG itself was well tolerated and had no negative influence on the healing behavior. Due to the favorable properties (highly adhesive, injectable, biocompatible) VPGs are a very interesting option for biologic augmentation. The study may serve as basis for further research in growth factor application models.
authors.affiliation: Department of Orthopaedic Sports Medicine, Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr., 81675, Munich, Germany. stefan.buchmann@LRZ.tu-muenchen.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Buchmann
authors.affiliation: Department of Orthopaedic Sports Medicine, Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr., 81675, Munich, Germany. g_sandmann@hotmail.com.|Department of Traumatology, Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr. 22, 81675, Munich, Germany. g_sandmann@hotmail.com.
authors.forename: Gunther H
authors.initials: GH
authors.lastname: Sandmann
authors.affiliation: Department of Orthopaedic Sports Medicine, Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr., 81675, Munich, Germany. lwalz@gmx.de.|Clinical Trial Unit, University Hospital Basel, Schanzenstr. 55, Basel, Switzerland. lwalz@gmx.de.
authors.forename: Lars
authors.initials: L
authors.lastname: Walz
authors.affiliation: Department of Orthopaedic Sports Medicine, Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr., 81675, Munich, Germany. thomasreichel87@gmail.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reichel
authors.affiliation: Department of Orthopaedic Sports Medicine, Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr., 81675, Munich, Germany. beitzelknut@tum.de.
authors.forename: Knut
authors.initials: K
authors.lastname: Beitzel
authors.affiliation: Department of Experimental Oncology, Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr. 22, 81675, Munich, Germany. gabriele.wexel@LRZ.tu-muenchen.de.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Wexel
authors.affiliation: Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig Maximilians University, Butenandstr. 5-13, 81377, Munich, Germany. weiwei.tian@cup.uni-muenchen.de.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tian
authors.affiliation: Institute for Pathology and Cytodiagnostics, Urselerstr. 33, 61348, Bad Homburg, v.d.H, Germany. batcave66@gmx.de.
authors.forename: Achim
authors.initials: A
authors.lastname: Battmann
authors.affiliation: Department of Orthopaedic Sports Medicine, Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr., 81675, Munich, Germany. stephan.vogt@LRZ.tu-muenchen.de.|Clinic for Orthopaedic Sports Medicine and arthroscopic Surgery, Orthopaedic Hospital Hessing Stiftung, Hessingstraße 17, 86199, Augsburg, Germany. stephan.vogt@LRZ.tu-muenchen.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Vogt
authors.affiliation: Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig Maximilians University, Butenandstr. 5-13, 81377, Munich, Germany. gerhard.winter@lrz.uni-muenchen.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Winter
authors.affiliation: Department of Orthopaedic Sports Medicine, Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr., 81675, Munich, Germany. a.imhoff@LRZ.tu-muenchen.de.
authors.forename: Andreas B
authors.initials: AB
authors.lastname: Imhoff
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002626:Chemistry, Pharmaceutical; D003094:Collagen / Q000096:biosynthesis; D003131:Combined Modality Therapy; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004337:Drug Carriers; D004355:Drug Stability; D005782:Gels; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D007700:Kinetics; D019637:Orthopedic Procedures; D010743:Phospholipids / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D017006:Rotator Cuff / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D000070636:Rotator Cuff Injuries; D012995:Solubility; D013708:Tendon Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005782:Gels; D010743:Phospholipids; D016179:Granulocyte Colony-Stimulating Factor; D003094:Collagen