Effects of Release of TSG-6 from Heparin Hydrogels on Supraspina
Tissue Engineering Part A
Pearson JJ, Mao J, Temenoff JS
Muscle degeneration after rotator cuff tendon tear is a significant clinical problem. In these experiments, we developed a poly(ethylene glycol)-based injectable granular hydrogel containing two heparin derivatives (fully sulfated [Hep] and fully desulfated [Hep−]) as well as a matrix metalloproteinase-sensitive peptide to promote sustained release of tumor necrosis factor–stimulated gene 6 (TSG-6) over 14+ days in vivo in a rat model of rotator cuff muscle injury. The hydrogel formulations demonstrated similar release profiles in vivo, thus facilitating comparisons between delivery from heparin derivatives on the level of tissue repair in two different areas of muscle (near the myotendious junction [MTJ] and in the muscle belly [MB]) that have been shown previously to have differing responses to rotator cuff tendon injury. We hypothesized that sustained delivery of TSG-6 would enhance the anti-inflammatory response following rotator cuff injury…
Biomaterials for Cell Manufacturing
ACS Macro Letters
Miller RC, Temenoff JS
Cell therapies, potent populations of cells used to treat disease and injury, can be strategically manufactured with biomaterial intervention to improve clinical translation. In this viewpoint, we discuss biomaterial design and integration into cell manufacturing steps to achieve three main goals: scale-up, phenotype control, and selection of potent cells. Material properties can be engineered to influence the cell−biomaterial interface and, therefore, impart desirable cell behavior such as growth, secretory activity, and differentiation. Future directions for the field should capitalize on the combinatorial design of biomaterial properties to yield highly specific and potent cell populations. Furthermore, future biomaterials could contribute to novel high-throughput cell separation technologies that can individually select the most therapeutically relevant cells within a produced batch.
Development and Characterization of Heparin-Containing Hydrogel/3D-Printed Scaffold Composites for Craniofacial Reconstruction
Annals of Biomedical Engineering
Brown NE, Ellerbe LR, Hollister SJ, Temenoff JS
Regeneration of cartilage and bone tissues remains challenging in tissue engineering due to their complex structures, and the need for both mechanical support and delivery of biological repair stimuli. Therefore, the goal of this study was to develop a composite scaffold platform for anatomic chondral and osteochondral repair using heparin-based hydrogels to deliver small molecules within 3D-printed porous scaffolds that provide structure, stiffness, and controlled biologic delivery. We designed a mold-injection system to combine hydrolytically degradable hydrogels and 3D-printed scaffolds…
Bone marrow mobilization & local SDF-1α delivery enhances nascent supraspinatus muscle fiber growth
Tissue Engineering Part A
Anderson LE, Tellier LE, Shah KR, Pearson JJ, Brimeyer AL, Botchwey EA, Temenoff JS
Rotator cuff tear is a significant problem that leads to poor clinical outcomes due to muscle degeneration after injury. The objective of this study was to synergistically increase the number of pro-regenerative cells recruited to injured rotator cuff muscle through a novel dual treatment system, consisting of a bone marrow mobilizing agent (VPC01091), hypothesized to “push” pro-healing cells into the blood, and localized delivery of Stromal cell-derived factor 1α (SDF-1α), to “pull” the cells to the injury site. Immediately after rotator cuff tendon injury in rat, the mobilizing agent was delivered systemically…
Poly(ethylene glycol)-Based Hydrogel Microcarriers Alter Secretory Activity of Genetically Modified Mesenchymal Stromal Cells
ACS Biomaterials Science & Engineering
Doron G, Wood L, Guldberg RE, Temenoff JS
In order to scale up culture therapeutic cells, such as mesenchymal stromal cells (MSCs), culture in suspension bioreactors using microcarriers (μCs) is preferred. However, the impact of microcarrier type on the resulting MSC secretory activity has not been investigated. In this study, two poly(ethylene glycol) hydrogel formulations with different swelling ratios…
Microfluidic Platform for Microparticle Fabrication and Release of a Cathepsin Inhibitor
Tissue Engineering Part C: Methods
Treviño EA, Shah J, Pearson JJ, Platt MO, Xia Y, Temenoff JS
Cathepsins are a family of cysteine proteases responsible for a variety of homeostatic functions throughout the body, including extracellular matrix remodeling, and have been implicated in a variety of degenerative diseases. However, clinical trials using systemic administration of cathepsin inhibitors have been abandoned due to side effects, so local delivery of cathepsin inhibitors may be advantageous. In these experiments, a novel microfluidic device platform was developed…
Development and characterization of Factor Xa-responsive materials for applications in cell culture and biologics delivery
Journal of Biomedical Materials Research A
Doron G, Pearson JJ, Guldberg RE, Temenoff JS
Stimuli–responsive biomaterials may be used to better control the release of bioactive molecules or cells for applications involving drug delivery and controlled cell release. In this study, we developed a Factor Xa (FXa)-responsive biomaterial capable of controlled release of pharmaceutical agents and cells from in vitro culture. We demonstrate…
Growth Factor Immobilization Strategies for Musculoskeletal Disorders
Current Osteoporosis Reports
Pearson JJ, Temenoff JS
Tissue regenerative solutions for musculoskeletal disorders have become increasingly important with a growing aged population. Current growth factor treatments often require high dosages with the potential for off-target effects. Growth factor immobilization strategies offer approaches towards alleviating these concerns. This review summarizes…
Injection of Micronized Human Amnion/Chorion Membrane in Increased Early Supraspinatus Muscle Regeneration in a Chronic Model of Rotator Cuff Tear
Annals of Biomedical Engineering
Anderson LE, Pearson JJ, Brimeyer AL, Temenoff JS
Surgical repair of severe rotator cuff tear often results in retear due to unaddressed muscle degeneration. The objective of this study was to test the regenerative potential of micronized dehydrated Human Amnion/Chorion Membrane (dHACM), in a clinically relevant delayed reattachment model of rotator cuff repair…
Hydrogel Culture Surface Stiffness Modulates Mesenchymal Stromal Cell Secretome and Alters Senescence
Tissue Engineering Part A
Ogle ME, Doron G, Levy MJ, Temenoff JS
Current cell culture surfaces used for the expansion and production of mesenchymal stromal cells (MSCs) are not optimized for the production of highly secretory and nonsenescent cells. In this study, we used poly (ethylene glycol) hydrogel substrates with tunable mechanical and biochemical properties to screen the effect of culture surfaces on pro-regenerative secretome by multiplex enzyme-linked immunosorbent assay, proliferation by PicoGreen DNA analysis, and senescence by senescence-associated β-galactosidase activity. We demonstrate that MSCs…
Multiomics characterization of mesenchymal stromal cells cultured in monolayer and as aggregates
Biotechnology and Bioengineering
Doron G, Klontzas ME, Mantalaris A, Guldberg RE, Temenoff JS
Mesenchymal stromal cells (MSCs) have failed to consistently demonstrate their therapeutic efficacy in clinical trials, due in part to variability in culture conditions used for their production. Of various culture conditions used for MSC production, aggregate culture has been shown to improve secretory capacity (a putative mechanism of action in vivo) compared with standard monolayer culture. The purpose of this study was to…
Special issue on Drug Delivery for Musculoskeletal Applications
Acta Biomaterialia
Temenoff JS, Hastings R
In the U.S. in 2015, 124 million adults reported suffering from a musculoskeletal-related health condition. These injuries have a significant impact on quality of life, as well as pose a significant economic burden, with an average of 10 days of work missed annually for those with musculoskeletal-related injuries…
Sequential, but not Concurrent, Incubation of Cathepsin K and L with Type I Collagen Results in Extended Proteolysis
Scientific Reports
Parks AN, Nahata J, Edouard NE, Temenoff JS, Platt MO
Degradation of extracellular matrix (ECM) during tendinopathy is, in part, mediated by the collagenolytic cathepsin K (catK) and cathepsin L (catL), with a temporal component to their activity. The objective of this study was to determine how catK and catL act in concert or in conflict to degrade collagen and tendon ECM during tissue degeneration…
Full-thickness Rotator Cuff Tear in Rat Results in Distinct Temporal Expression of
Multiple Proteases in Tendon, Muscle and Cartilage
Journal of Orthopaedic Research
Trevino EA, McFaline-Figueroa J, Guldberg RE, Platt MO, Temenoff JS
The etiology of joint tissue degeneration following rotator cuff tear remains unclear. Thus, the purpose of this study was to understand the timeline of protease activity in the soft tissues of the shoulder (tendon, muscle, and cartilage) that may lead to down-stream degeneration…
Localized SDF-1α Delivery Increases Pro-Healing Bone Marrow-Derived Cells in the Supraspinatus Muscle Following Severe Rotator Cuff Injury
Regenerative Engineering and Translational Medicine
Tellier LE, Krieger JR, Brimeyer AL, Coogan AC, Falis AA, Rinker TE, Schudel A, Thomas SN, Jarrett CD, Willett NJ, Botchwey EA, Temenoff JS
To examine how the chemotactic agent stromal cell-derived factor-1alpha (SDF-1α) modulates the unique cellular milieu within rotator cuff muscle following tendon injury, we developed an injectable, heparin-based microparticle platform to locally present SDF-1α within the supraspinatus muscle following severe rotator cuff injury…
Intra-articular TSG-6 delivery from heparin-based microparticles reduces cartilage damage in a rat model of osteoarthritis
Biomaterials Science
Tellier LE, Trevino EA, Brimeyer AL, Reece DS, Willet NJ, Guldberg RE, Temenoff JS
As a potential treatment for osteoarthritis (OA), we have developed injectable and hydrolytically degradable heparin-based biomaterials with tunable sulfation for the intra-articular delivery of tumor necrosis factor-alpha stimulated gene-6 (TSG-6), a protein known to inhibit plasmin which may degrade extracellular matrix within OA joints…
Combination of Heparin Binding Peptide and Heparin Cell Surface Coatings for Mesenchymal Stem Cell Spheroid Assembly
Bioconjugate Chemistry
Lei J, Murphy WL, Temenoff JS
Microtissues containing multiple cell types have been used in both in vitro models and in vivo tissue repair applications. However, to improve throughput, there is a need to develop a platform that supports self-assembly of a large number of 3D microtissues containing multiple cell types in a dynamic suspension system. Thus, the objective of this study was to exploit the binding interaction between the negatively charged glycosaminoglycan, heparin, and a known heparin binding peptide to establish a method that promotes assembly of mesenchymal stem cell (MSC) spheroids into larger aggregates…
Microparticle-mediated sequestration of cell-secreted proteins to modulate chondrocytic differentiation
Acta Biomaterialia
Rinker TE, Philbrick BD, Hettiaratchi MH, Smalley DM, McDevitt TC, Temenoff JS
Protein delivery is often used in tissue engineering applications to control differentiation processes, but is limited by protein instability and cost. An alternative approach is to control the cellular microenvironment through biomaterial-mediated sequestration of cell-secreted proteins important to differentiation. Thus, we utilized heparin-based microparticles to modulate cellular differentiation via protein sequestration in an in vitro model system of endochondral ossification…
Core-shell microparticles for protein sequestration and controlled release of a protein-laden core
Acta Biomaterialia
Rinker TE, Philbrick BD, Temenoff JS
Development of multifunctional biomaterials that sequester, isolate, and redeliver cell-secreted proteins at a specific timepoint may be required to achieve the level of temporal control needed to more fully regulate tissue regeneration and repair. In response, we fabricated core-shell heparin-poly(ethylene-glycol) (PEG) microparticles (MPs) with a degradable PEG-based shell that can…
Supraspinatus tendon overuse results in degenerative changes to tendon insertion region and adjacent humeral cartilage in a rat model
Journal of Orthopedic Research
Parks AN, McFaline-Figueroa J, Coogan A, Poe-Yamagata E, Guldberg RE, Platt MO, Temenoff JS
The etiology of rotator cuff tendon overuse injuries is still not well understood. Furthermore, how this overuse injury impacts other components of the glenohumeral joint, including nearby articular cartilage, is also unclear. Therefore, this study sought to better understand the time course of tendon protease activity in a rat model of supraspinatus overuse, as well as…
Cyclic tension promotes fibroblastic differentiation of human MSCs cultured on collagen-fibre scaffolds
Journal of Tissue Engineering and Regenerative Medicine
Qiu Y, Lei J, Koob TJ, Temenoff JS.
Mesenchymal stem cells (MSCs) have been suggested as a potential cell source for tendon/ligament tissue engineering. Extrinsic cues, such as the chemical and physical properties of scaffolds, as well as external forces, play an important role in fibroblastic differentiation…
Heparin-based hydrogels with tunable sulfation & degradation for anti-inflammatory small molecule delivery
Biomaterials Science
Peng Y, Tellier LE, Temenoff JS
Sustained release of anti-inflammatory agents remains challenging for small molecule drugs due to their low molecular weight and hydrophobicity. Therefore, the goal of this study was to control the release of a small molecule anti-inflammatory agent, crystal violet (CV), from hydrogels fabricated with heparin…
Cell number and chondrogenesis in human mesenchymal stem cell aggregates is affected by the sulfation level of heparin used as a cell coating
Journal of Biomedical Research Materials
Lei J, Trevino E, Temenoff JS
For particular cell-based therapies, it may be required to culture mesenchymal stem cell (MSC) aggregates with growth factors to promote cell proliferation and/or differentiation. Heparin, a negatively charged glycosaminoglycan (GAG) is known…
Cell Surface Access Is Modulated by Tethered Bottlebrush Proteoglycans
Biophysical Journal
Chang PS, McLane LT, Fogg R, Scrimgeour J, Temenoff JS, Granqvist A, Curtis JE
The hyaluronan-rich pericellular matrix (PCM) plays physical and chemical roles in biological processes ranging from brain plasticity, to adhesion-dependent phenomena such as cell migration, to the onset of cancer. This study investigates how the spatial distribution of the large negatively charged bottlebrush proteoglycan, aggrecan, impacts PCM morphology and cell surface access…
Special Collection: Emerging Concepts in Three-Dimensional Microtissues
Tissue Engineering
Temenoff JS
Over the past decade, the concept of tissue engineering has been extended to include technologies that use multicellular aggregates, not only to repair or replace tissue but also as a stand-alone in vitro device…
Hydrolysis and Sulfation Pattern Effects on Release of Bioactive Bone Morphogenetic Protein-2 from Heparin-Based Microparticles
Journal of Materials Chemistry B
Tellier LE, Miller T, McDevitt TC, Temenoff JS
Glycosaminoglycans (GAGs) such as heparin are promising materials for growth factor delivery due to their ability to efficiently bind positively charged growth factors including bone morphogenetic protein-2 (BMP-2) through their negatively charged sulfate groups. Therefore, the goal of this study was to examine BMP-2 release from heparin-based microparticles (MPs)…
Cathepsins in Rotator Cuff Tendinopathy: Identification in Human Chronic Tears and Temporal Induction in a Rat Model
Annals of Biomedical Engineering
Seto SP, Parks AN, Qiu Y, Soslowsky LJ, Karas S, Platt MO, Temenoff JS
While overuse of the supraspinatus tendon is a leading factor in rotator cuff injury, the underlying biochemical changes have not been fully elucidated. In this study, torn human rotator cuff (supraspinatus) tendon tissue was analyzed for the…
PubMed
Effect of selective heparin desulfation on preservation of bone morphogenetic protein-2 bioactivity after thermal stress
Bioconjugate Chemistry
Seto SP, Miller T, Temenoff JS
Bone morphogenetic protein-2 (BMP-2) plays an important role in bone and cartilage formation and is of interest in regenerative medicine. Heparin can interact electrostatically with BMP-2 and thus has been explored for controlled release and potential stabilization of this growth factor in vivo. However,…
Heparin microparticle effects on presentation and bioactivity of bone morphogenetic protein-2
Biomaterials
Hettiaratchi MH, Miller T, Temenoff JS, Guldberg RE, McDevitt TC
Biomaterials capable of providing localized and sustained presentation of bioactive proteins are critical for effective therapeutic growth factor delivery. However, current biomaterial delivery vehicles commonly suffer from limitations that can…
PubMed
Molecular engineering of glycosaminoglycan chemistry for biomolecule delivery
Acta Biomaterialia
Miller T, Goude MC, McDevitt TC, Temenoff JS
Glycosaminoglycans (GAGs) are linear, negatively charged polysaccharides that interact with a variety of positively charged growth factors. In this review article the effects of engineering GAG chemistry for molecular delivery applications in…
PubMed
Interactions between mesenchymal stem cells, adipocytes, and osteoblasts in a 3D tri-culture model of hyperglycemic conditions in the bone marrow microenvironment
Integrative Biology
Rinker TE, Hammoudi TM, Kemp ML, Lu H, Temenoff JS
Recent studies have found that uncontrolled diabetes and consequential hyperglycemic conditions can lead to an increased incidence of osteoporosis. Osteoblasts, adipocytes, and mesenchymal stem cells (MSCs) are all components of the bone marrow…
PubMed
Chondroitin Sulfate Microparticles Modulate Transforming Growth Factor-β1-Induced Chondrogenesis of Human Mesenchymal Stem Cell Spheroids
Cells Tissues Organs
Goude MC, McDevitt TC, Temenoff JS
Mesenchymal stem cells (MSCs) have been previously explored as a part of cell-based therapies for the repair of damaged cartilage. Current MSC chondrogenic differentiation strategies employ large pellets; however, we have developed a technique to…
PubMed
Biological properties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing.
International Wound Journal
Koob TJ, Rennert R, Zabek N, Massee M, Lim JJ, Temenoff JS, Li WW, Gurtner G
Human amnion/chorion tissue derived from the placenta is rich in cytokines and growth factors known to promote wound healing; however, preservation of the biological activities of therapeutic allografts during processing remains a challenge. In…
PubMed
The effect of desulfation of chondroitin sulfate on interactions with positively charged growth factors and upregulation of cartilaginous markers in encapsulated MSCs
Biomaterials
Lim JJ, Temenoff JS
Sulfated glycosaminoglycans (GAGs) are known to interact electrostatically with positively charged growth factors to modulate signaling. Therefore, regulating the degree of sulfation of GAGs may be a promising approach to tailor biomaterial…
PubMed
Development of 3D hydrogel culture systems with on-demand cell separation
Biotechnology Journal
Hamilton SK, Bloodworth NC, Massad CS, Hammoudi TM, Suri S, Yang PJ, Lu H, Temenoff JS
Recently there has been an increased interest in the effects of paracrine signaling between groups of cells, particularly in the context of better understanding how stem cells contribute to tissue repair. Most current 3D co-culture methods lack…
PubMed
Modulation of mesenchymal stem cell shape in enzyme-sensitive hydrogels is decoupled from upregulation of fibroblast markers under cyclic tension
Tissue Engineering Part A.
Yang PJ, Levenston ME, Temenoff JS
Our laboratory has developed a tensile culture bioreactor as a system for understanding mesenchymal stem cell (MSC) differentiation toward a tendon/ligament fibroblast phenotype in response to cyclic tensile strain. In this study, we investigated…
PubMed
Three-dimensional in vitro tri-culture platform to investigate effects of crosstalk between mesenchymal stem cells, osteoblasts, and adipocytes
Tissue Engineering Part A.
Hammoudi TM, Rivet CA, Kemp ML, Lu H, Temenoff JS
The bone marrow niche for mesenchymal stem cells (MSCs) contains different amounts of bone and fat that vary with age and certain pathologies. How this dynamic niche environment may affect their differentiation potential and/or healing properties…
PubMed
Differentiation of mesenchymal stem cells in heparin-containing hydrogels via coculture with osteoblasts
Cell and Tissue Research
Song SP, Casas ME, Temenoff JS.
The therapeutic potency of delivered mesenchymal stem cells (MSCs) in tissue engineering applications may be improved by priming cells toward a differentiated state via coculture with native, differentiated cells prior to implantation; however,…
PubMed
2011 panel on developing a biomaterials curriculum
Journal of Biomedical Materials Research
Reichert WM, Harris TR, Lemons J, Mikos AG, Puleo DA, Schoen FJ, Temenoff JS
This article provides the transcript for the Panel on Developing a Biomaterials Curriculum held at the 2011 annual meeting of the Society for Biomaterials in Orlando, FL. The panelists were Thomas R. Harris of Vanderbilt University, Jack Lemons…
PubMed
PEG-based hydrogels with tunable degradation characteristics to control delivery of marrow stromal cells for tendon overuse injuries
Acta Biomaterialia
Qiu Y, Lim JJ, Scott L Jr, Adams RC, Bui HT, Temenoff JS.
Marrow stromal cells (MSCs) have been suggested as a means to improve healing in tendon overuse injuries (tendinopathy), but optimal delivery methods for these cells have yet to be determined. In this study novel degradable hydrogels based on…
PubMed
Development of nano- and micro-scale chondroitin sulfate particles for controlled growth factor delivery
Acta Biomaterialia
Lim JJ, Hammoudi TM, Bratt-Leal AM, Hamilton SK, Kepple KL, Bloodworth NC, McDevitt TC, Temenoff JS
Size scale plays an important role in the release properties and cellular presentation of drug delivery vehicles. Because negatively charged chondroitin sulfate (CS) is capable of electrostatically sequestering positively charged growth factors,…
PubMed
Aggregation of bovine anterior cruciate ligament fibroblasts or marrow stromal cells promotes aggrecan production
Biotechnology and Bioengineering
Lim JJ, Scott L Jr, Temenoff JS
The development of a tissue-engineered alternative for current ligament grafts requires the creation of a fibrocartilaginous interface between the engineered ligament midsubstance and bone tissue. Therefore, the focus of this study was to examine…
PubMed
Long-term spatially defined coculture within three-dimensional photopatterned hydrogels.
Tissue Engineering Part C: Methods
Hammoudi TM, Lu H, Temenoff JS
Spatially controlled coculture in three-dimensional environments that appropriately mimic in vivo tissue architecture is a highly desirable goal in basic scientific studies of stem cell physiological processes (e.g., proliferation, matrix…
PubMed
Cyclic tensile culture promotes fibroblastic differentiation of marrow stromal cells encapsulated in poly(ethylene glycol)-based hydrogels.
Tissue Engineering Part A
Doroski DM, Levenston ME, Temenoff JS
To inform future efforts in tendon/ligament tissue engineering, our laboratory has developed a well-controlled model system with the ability to alter both external tensile loading parameters and local biochemical cues to better understand marrow…
PubMed
Engineering orthopaedic tissue interfaces.
Tissue Engineering Part B: Methods
Yang PJ, Temenoff JS
While a wide variety of approaches to engineering orthopedic tissues have been proposed, less attention has been paid to the interfaces, the specialized areas that connect two tissues of different biochemical and mechanical properties. The…
PubMed
Degradative properties and cytocompatibility of a mixed-mode hydrogel containing oligo[poly(ethylene glycol) fumarate] and poly(ethylene glycol) dithiol.
Acta Biomaterialia
Brink KS, Yang PJ, Temenoff JS
Our laboratory is currently exploring synthetic oligo(poly(ethylene glycol)fumarate) (OPF)-based biomaterials as a means to deliver fibroblasts to promote regeneration of central/partial defects in tendons and ligaments. In order to further…
PubMed
Techniques for biological characterization of tissue-engineered tendon and ligament.
Biomaterials
Doroski DM, Brink KS, Temenoff JS
Injuries to tendons and ligaments are prevalent and result in a significant decrease in quality of patient life. Tissue-engineering strategies hold promise as alternatives to current treatments for these injuries, which often fail to fully…
Pub Med