title: Poly (glycerol sebacate) elastomer supports bone regeneration by its mechanical properties being closer to osteoid tissue rather than to mature bone.
abstract: Mechanical load influences bone structure and mass. Arguing the importance of load-transduction, we investigated the mechanisms inducing bone formation using an elastomeric substrate. We characterized Poly (glycerol sebacate) (PGS) in vitro for its mechanical properties, compatibility with osteoprogenitor cells regarding adhesion, proliferation, differentiation under compression versus static cultures and in vivo for the regeneration of a rabbit ulna critical size defect. The load-transducing properties of PGS were compared in vitro to a stiffer poly lactic-co-glycolic-acid (PLA/PGA) scaffold of similar porosity and interconnectivity. Under cyclic compression for 7days, we report focal adhesion kinase overexpression on the less stiff PGS and upregulation of the transcription factor Runx2 and late osteogenic markers osteocalcin and bone sialoprotein (1.7, 4.0 and 10.0 folds increase respectively). Upon implanting PGS in the rabbit ulna defect, histology and micro-computed tomography analysis showed complete gap bridging with new bone by the PGS elastomer by 8weeks while minimal bone formation was seen in empty controls. Immunohistochemical analysis demonstrated the new bone to be primarily regenerated by recruited osteoprogenitors cells expressing periostin protein during early phase of maturation similar to physiological endochondral bone development. This study confirms PGS to be osteoconductive contributing to bone regeneration by recruiting host progenitor/stem cell populations and as a load-transducing substrate, transmits mechanical signals to the populated cells promoting differentiation and matrix maturation toward proper bone remodeling. We hence conclude that the material properties of PGS being closer to osteoid tissue rather than to mineralized bone, allows bone maturation on a substrate mechanically closer to where osteoprogenitor/stem cells differentiate to develop mature load-bearing bone.
  
  
  
  The development of effective therapies for bone and craniofacial regeneration is a foremost clinical priority in the mineralized tissue engineering field. Currently at risk are patients seeking treatment for craniofacial diseases, traumas and disorders including birth defects such as cleft lip and palate, (1 in 525 to 714 live births), craniosynostosis (300-500 per 1,000,000 live births), injuries to the head and face (20 million ER visits per year), and devastating head and neck cancers (8000 deaths and over 30,000 new cases per year). In addition, approximately 6.2 million fractures occur annually in the United States, of which 5-10% fail to heal properly, due to delayed or non-union [1], and nearly half of adults aged 45-65 have moderate to advanced periodontitis with associated alveolar bone loss, which, if not reversed, will lead to the loss of approximately 6.5 teeth/individual [2]. The strategies currently available for bone loss treatment largely suffer from limitations in efficacy or feasibility, necessitating further development and material innovation. Contemporary materials systems themselves are indeed limited in their ability to facilitate mechanical stimuli and provide an appropriate microenvironment for the cells they are designed to support. We propose a strategy which aims to leverage biocompatibility, biodegradability and material elasticity in the creation of a cellular niche. Within this niche, cells are mechanically stimulated to produce their own extracellular matrix. The hypothesis that mechanical stimuli will enhance bone regeneration is supported by a wealth of literature showing the effect of mechanical stimuli on bone cell differentiation and matrix formation. Using mechanical stimuli, to our knowledge, has not been explored in vivo in bone tissue engineering applications. We thus propose to use an elastomeric platform, based on poly(glycerol sebacate (PGS), to mimic the natural biochemical environment of bone while enabling the transmission of mechanical forces. In this study we report the material's load-transducing ability as well as falling mechanically closer to bone marrow and osteoid tissue rather than to mature bone, allowed osteogenesis and bone maturation. Defying the notion of selecting bone regeneration scaffolds based on their relative mechanical comparability to mature bone, we consider our results in part novel for the new application of this elastomer and in another fostering for reassessment of the current selection criteria for bone scaffolds.
authors.affiliation: Center for Craniofacial Regeneration, Department of Oral Biology, University of Pittsburgh, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Zaky
authors.affiliation: Department of Bioengineering, University of Pittsburgh, USA.
authors.forename: K W
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, University of Pittsburgh, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Chemistry, University of Pittsburgh Dietrich School of Arts and Sciences, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jensen
authors.affiliation: Center for Craniofacial Regeneration, Department of Oral Biology, University of Pittsburgh, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, USA.
authors.forename: K
authors.initials: K
authors.lastname: Verdelis
authors.affiliation: Department of Bioengineering, University of Pittsburgh, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Craniofacial Regeneration, Department of Oral Biology, University of Pittsburgh, USA; Department of Bioengineering, University of Pittsburgh, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Almarza
authors.affiliation: Center for Craniofacial Regeneration, Department of Oral Biology, University of Pittsburgh, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, USA. Electronic address: csfeir@pitt.edu.
authors.forename: C
authors.initials: C
authors.lastname: Sfeir
mesh_terms: D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects*; D003651:Decanoates / Q000737:chemistry / Q000494:pharmacology; D020724:Elastomers / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019344:Lactic Acid / Q000737:chemistry / Q000494:pharmacology; D011100:Polyglycolic Acid / Q000737:chemistry / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D054457:Tissue Scaffolds / Q000737:chemistry*; D014457:Ulna / Q000293:injuries / Q000378:metabolism / Q000473:pathology
chemical_list: D003651:Decanoates; D020724:Elastomers; D011108:Polymers; C469892:poly(glycerol-sebacate); D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005990:Glycerol
keywords: Bone tissue engineering, poly (glycerol sebacate); Critical size defect; Load-transducing scaffold; Osteogenic differentiation; Osteoid