Repair of massive tendon defects occur in tens of thousands annually in the U.S. alone to restore the range of motion of involved joints. Autografts are the primary choice;however, donor site morbidity and limits in supply are significant issues. Allografts/xenografts may elicit immune response. Foreign body reaction to synthetic polymers is a significant drawback. Regenerative solutions expediting tendon repair, enabling earlier mobilization and reducing failure rates would be highly significant by reducing treatment costs. Tendon reconstruction faces multiple challenges due to the absence of a bioscaffold which unifies mechanical robustness, tenoinductivity and a form that enables integration to the repair site surgically. Supported in part by a R21 project, we developed a novel method to fabricate electrochemically aligned collagen (ELAC) threads whose fabric orientation, packing density and mechanical properties match those of the native tendon. ELAC induces tenogenic differentiation of mesenchymal stem cell (MSC) topographically and MSCs in woven scaffolds synthesize a matrix that is positive of collagen I and the tendon-specific tenomodulin molecule. ELAC is biocompatible in vivo and resolves into a tendon-like fibrous tissue. The degradation rate of ELAC matches the slow repair-rate of tendon. Therefore, ELAC is a unique bioactive and mechanically competent platform with the potential to repair tendon without the addition of growth factors. The proposed studies will test the hypothesis that the biomechanics of the tendon gap defects repaired by ELAC-based regenerative strategies will match or exceed that is attained by autografts.
The first aim will optimize ELAC topography and in vitro conditioning processes to maximize tenogenesis of MSCs in woven ELAC scaffolds. Specifically, Sub-Aim 1.1 will study the roles of substrate compaction, alignment and stiffness in eliciting the observed tenogenic response. Marrow- derived MSCs will be seeded on textures of random vs. aligned, electrocompacted vs. gel form, and matrix stiffness values modulated over six orders of magnitude (1 kPa to 1000 MPa), a range coverage that is unique to ELAC.
Sub Aim 1. 2 studies will optimize cell seeding density and invoke mechanostimulation to assess effects of strain amplitude and strain rate towards further enhancement of tenogenesis in vitro.
The second aim will improve the repair outcome on critical sized tendon defects by using woven ELAC scaffolds. A rabbit infraspinatus tendon defect model will be employed. The treatment groups will include autograft repair, ELAC scaffolds (with and without cells) and gap-defect as the negative control. Outcome measures will include repair biomechanics, types of de novo matrix molecules, inflammatory response and healing morphology. Elucidation of material-based and in vitro conditioning based cues in tenogenesis and in depth validation of its merits using the rabbit model will pave the way for a preclinical assessment of this novel biomaterial in large animal models. If ELAC performs at least as good as autografts the costs and morbidity associated with autografts will be eliminated. ELAC will benefit patients by restoring joint range of motion and by eliminating revision surgeries.

Public Health Relevance

Massive injuries of tendons call for engineered tissues in the bulk form to repair the gap defects. The proposed studies will develop scaffolds from a collagen-based novel biomaterial that is processed to mimic tendon. The differentiation of adult stem cells on these scaffolds will be maximized and scaffold-cell systems will be applied to restore the strength of injured tendons using an animal model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR063701-01A1
Application #
8697319
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2014-04-08
Project End
2019-03-31
Budget Start
2014-04-08
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$282,483
Indirect Cost
$99,273
Name
Case Western Reserve University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106