The ultimate goal of this proposal is to develop an innovative and modular technology for osteochondral tissue repair comprising injectable, thermally responsive, in situ forming, and biodegradable hydrogel constructs capable of sustaining the delivery of encapsulated chondrogenic and osteogenic cell populations in a spatially directed fashion to promote native tissue regeneration. We hypothesize that a cytocompatible hydrogel system consisting of non-shrinking, injectable hydrogels with fully soluble degradation products will be formed through the combination of custom poly(N-isopropylacrylamide)-based thermogelling macromers and lysine-based crosslinking macromers that also contain sites for covalent attachment of chondroitin sulfate (CS) to enhance the integration of resultant constructs. Additionally, we hypothesize that the incorporation of poly(L-lysine) (PLL) within the thermogelling hydrogel will enhance the chondrogenic capacity of co-encapsulated articular chondrocyte and mesenchymal stem cell (AC-MSC) cocultures via the induction of developmentally relevant condensation signals. Finally, we hypothesize that a bilayered construct combining the CS-modified chondrogenic hydrogel layer with an osteogenic hydrogel layer of designer mineralizing capability will be leveraged to promote effective osteochondral tissue repair.
Three Specific Aims are proposed to address these hypotheses. First, a lysine-based polyesterurethane macromer comprising a biodegradable poly(DL-lactic-co- glycolic acid) mid-block and chemically crosslinkable diamine functionalities will be developed, covalently modified with CS, combined with the thermogelling macromer and thoroughly assessed to establish structure- property relationships. Second, PLL will be incorporated into the hydrogels and its effects on the chondrogenesis of encapsulated AC-MSC cocultures will be evaluated. Further, the combined effects of PLL presentation, AC-MSC coculture, and CS-modification of hydrogel constructs on cartilage tissue integration will be also evaluated ex vivo. Third, the hydrogels developed in Specific Aim 1 and optimized for chondrogenic potential in Specific Aim 2 will be merged with hydrogel formulations with high mineralizing capability to yield bilayered hydrogel constructs comprising chondrogenic and osteogenic layers for the effective repair of osteochondral defects. The potential synergistic effects of encapsulated cells in the osteogenic and chondrogenic layers with PLL delivery will be evaluated in vitro and in vivo to determine the most effective configuration for osteochondral tissue repair in a well-established rabbit osteochondral defect model. The proposed system will address persisting significant challenges associated with osteochondral defect repair by enabling stable integration of the construct with the surrounding native cartilage tissue through a highly modular two-component design, while promoting the chondrogenic and osteogenic differentiation of respective cell populations delivered to effect both cartilage and bone regeneration, respectively.

Public Health Relevance

With limited natural capacity for regeneration, damaged cartilage loses its characteristic mechanical and frictionless properties, which compromise its ability to enable frictionless bone articulation in major synovial joints. As such, millions of afflicted patients perpetuate the growing annual demand for cartilage repair therapies and continue to present a significant economical burden on society. We propose the development of an injectable, modular system that can be formed and integrated within joint defects in situ for the spatially controlled delivery of cartilage progenitor cells coupled with a biomolecule that stimulates their key cell-cell interactions and bone progenitor cells to promote tissue regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR068073-01A1
Application #
9036736
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2015-09-15
Project End
2020-08-31
Budget Start
2015-09-15
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$331,898
Indirect Cost
$111,898
Name
Rice University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
Bittner, Sean M; Guo, Jason L; Melchiorri, Anthony et al. (2018) Three-dimensional Printing of Multilayered Tissue Engineering Scaffolds. Mater Today (Kidlington) 21:861-874
Tatara, Alexander M; Kontoyiannis, Dimitrios P; Mikos, Antonios G (2018) Drug delivery and tissue engineering to promote wound healing in the immunocompromised host: Current challenges and future directions. Adv Drug Deliv Rev 129:319-329
Kim, Yu Seon; Smoak, Mollie M; Melchiorri, Anthony J et al. (2018) An Overview of the Tissue Engineering Market in the United States from 2011 to 2018. Tissue Eng Part A :
Trachtenberg, Jordan E; Placone, Jesse K; Smith, Brandon T et al. (2017) Extrusion-based 3D printing of poly(propylene fumarate) scaffolds with hydroxyapatite gradients. J Biomater Sci Polym Ed 28:532-554
Du, Yingying; Liu, Haoming; Yang, Qin et al. (2017) Selective laser sintering scaffold with hierarchical architecture and gradient composition for osteochondral repair in rabbits. Biomaterials 137:37-48
Bracaglia, Laura G; Smith, Brandon T; Watson, Emma et al. (2017) 3D printing for the design and fabrication of polymer-based gradient scaffolds. Acta Biomater 56:3-13
Lee, Esther J; Huh, Beom Kang; Kim, Se Na et al. (2017) Application of Materials as Medical Devices with Localized Drug Delivery Capabilities for Enhanced Wound Repair. Prog Mater Sci 89:392-410
Vo, Tiffany N; Tatara, Alexander M; Santoro, Marco et al. (2017) Acellular mineral deposition within injectable, dual-gelling hydrogels for bone tissue engineering. J Biomed Mater Res A 105:110-117
Tatara, Alexander M; Mikos, Antonios G (2016) Tissue Engineering in Orthopaedics. J Bone Joint Surg Am 98:1132-9
Lu, Steven; Lee, Esther J; Lam, Johnny et al. (2016) Evaluation of Gelatin Microparticles as Adherent-Substrates for Mesenchymal Stem Cells in a Hydrogel Composite. Ann Biomed Eng 44:1894-907

Showing the most recent 10 out of 14 publications