title: Heparinized collagen sutures for sustained delivery of PDGF-BB: Delivery profile and effects on tendon-derived cells In-Vitro.
abstract: Suturing is the standard of repair for lacerated flexor tendons. Past studies focused on delivering growth factors to the repair site by incorporating growth factors to nylon sutures which are commonly used in the repair procedure. However, conjugation of growth factors to nylon or other synthetic sutures is not straightforward. Collagen holds promise as a suture material by way of providing chemical sites for conjugation of growth factors. On the other hand, collagen also needs to be reconstituted as a mechanically robust thread that can be sutured. In this study, we reconstituted collagen solutions as suturable collagen threads by using linear electrochemical compaction. Prolonged release of PDGF-BB (Platelet derived growth factor-BB) was achieved by covalent bonding of heparin to the collagen sutures. Tensile mechanical tests of collagen sutures before and after chemical modification indicated that the strength of sutures following chemical conjugation stages was not compromised. Strength of lacerated tendons sutured with epitendinous collagen sutures (11.2±0.7N) converged to that of the standard nylon suture (14.9±2.9N). Heparin conjugation of collagen sutures didn't affect viability and proliferation of tendon-derived cells and prolonged the PDGF-BB release up to 15days. Proliferation of cells seeded on PDGF-BB incorporated collagen sutures was about 50% greater than those seeded on plain collagen sutures. Collagen that is released to the media by the cells increased by 120% under the effects of PDGF-BB and collagen production by cells was detectable by histology as of day 21. Addition of PDGF-BB to collagen sutures resulted in a moderate decline in the expression of the tendon-associated markers scleraxis, collagen I, tenomodulin, and COMP; however, expression levels were still greater than the cells seeded on collagen gel. The data indicate that the effects of PDGF-BB on tendon-derived cells mainly occur through increased cell proliferation and that longer term studies are needed to confirm whether this proliferation is outweighs the moderate reduction in the expression of tendon-associated genes.
  
  
  
  A mechanically robust pure collagen suture was fabricated via linear electrocompaction and conjugated with heparin for prolonged delivery of PDFG-BB. Sustained delivery of the PDGF-BB improved the proliferation of tendon derived cells substantially at the expense of a moderate downregulation of tenogenic markers. The collagen threads were functionally applicable as epitendinous sutures when applied to chicken flexor tendons in vitro. Overall, electrocompacted collagen sutures holds potential to improve repair outcome in flexor tendon surgeries by improving cellularity and collagen production through delivery of the PDGF-BB. The bioinductive suture concept can be applied to deliver other growth factors for a wide-array of applications.
authors.affiliation: Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, United States.
authors.forename: Mousa
authors.initials: M
authors.lastname: Younesi
authors.affiliation: Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, United States.
authors.forename: Baris Ozgur
authors.initials: BO
authors.lastname: Donmez
authors.affiliation: Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, United States.
authors.forename: Anowarul
authors.initials: A
authors.lastname: Islam
authors.affiliation: Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, United States; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, United States; Department of Orthopedics, Case Western Reserve University, Cleveland, OH 44106, United States. Electronic address: ozan.akkus@case.edu.
authors.forename: Ozan
authors.initials: O
authors.lastname: Akkus
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002645:Chickens; D003094:Collagen / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems / Q000379:methods*; D006493:Heparin / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D013194:Staining and Labeling; D013537:Sutures; D013710:Tendons / Q000166:cytology*; D013718:Tensile Strength
chemical_list: D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D006493:Heparin; D003094:Collagen
keywords: Aligned collagen suture; Electrochemical compaction; Flexor tendon repair; Growth factor delivery; Heparin