@article{gaffney_fisher_freytes_2023, title={Tendon Extracellular Matrix Promotes Myotendinous Junction Protein Expression in Engineered Muscle Tissue under Both Static and Mechanically Stimulated Culture Conditions}, volume={2023}, ISSN={["1932-7005"]}, DOI={10.1155/2023/6658543}, abstractNote={Studying the crosstalk between the muscle and tendon tissue is an important yet understudied area in musculoskeletal research. In vitro models can help elucidate the function and repair of the myotendinous junction (MTJ) under static and dynamic culture conditions using engineered muscle tissues. The goal of this study was to culture engineered muscle tissues in a novel bioreactor in both static and mechanically stimulated cultures and evaluate the expression of MTJ-specific proteins within the muscle-tendon unit(paxillin and type XXII collagen). C2C12 myoblasts were seeded in hydrogels made from type I collagen ortendon-derived extracellular matrix (tECM) and allowed to form around movable anchors. Engineered tissues were allowed to form and stabilize for 10 days. After 10 days in the culture, stimulated cultures were cyclically stimulated for 3 hours per day for 2 and 4 weeks alongside static cultures. Strain values at the maximum displacement of the anchors averaged about 0.10, a target that has been shown to induce myogenic phenotype in C2C12s. Protein expression of paxillin after 2 weeks did not differ between hydrogel materials in static cultures but increased by 62% in tECM when mechanically stimulated. These differences continued after 4 weeks, with 31% and 57% increases in tECM tissues relative to type I collagen. Expression of type XXII collagen was similarly influenced by hydrogel material and culture conditions. Overall, this research combined a relevant microenvironment to study muscle and tendon interactions with a novel bioreactor to apply mechanical strain, an important regulator of the formation and maintenance of the native MTJ.}, journal={JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE}, author={Gaffney, Lewis S. and Fisher, Matthew B. and Freytes, Donald O.}, year={2023}, month={Aug} }
 @article{detwiler_polkoff_gaffney_freytes_piedrahita_2022, title={Donor Age and Time in Culture Affect Dermal Fibroblast Contraction in an In Vitro Hydrogel Model}, volume={8}, ISSN={["1937-335X"]}, DOI={10.1089/ten.tea.2021.0217}, abstractNote={Current cellular hydrogel-based skin grafts composed of human dermal fibroblasts and a hydrogel scaffold tend to minimize contraction of full-thickness skin wounds and support skin regeneration. However, there has been no comparison between the sources of the dermal fibroblast used. Products using human adult or neonatal foreskin dermal fibroblasts are often expanded in vitro and used after multiple passages without a clear understanding of the effects of this initial production step on the quality and reproducibility of the cellular behavior. Based on the known effects of 2D tissue culture expansion on cellular proliferation and gene expression, we hypothesized that differences in donor age and time in culture may influence cellular properties and contractile behavior in a fibroblast-populated collagen matrix. Using porcine skin as a model based on its similarity to human skin in structure and wound healing properties, we isolated porcine dermal fibroblasts of three different donor ages for use in a 2D proliferation assay and in a 3D cell-populated collagen matrix contractility assay. In 2D cell culture, doubling time remained relatively consistent between all age groups from passage 1 to 6. In the contractility assays, fetal and neonatal groups contracted faster and generated more contractile force than the adult group at passage 1 in vitro. However, after five passages in culture, there was no difference in contractility between ages. These results show how cellular responses in a hydrogel scaffold differ based on donor age and time in culture in vitro, and suggest that consistency in the cellular component of bioengineered skin products could be beneficial in the biomanufacturing of consistent, reliable skin grafts and graft in vivo models. Future research and therapies using bioengineered skin grafts should consider how results may vary based on donor age and time in culture before seeding.}, journal={TISSUE ENGINEERING PART A}, author={Detwiler, Amber and Polkoff, Kathryn and Gaffney, Lewis and Freytes, Donald O. and Piedrahita, Jorge A.}, year={2022}, month={Aug} }
 @article{chiu_duffy_chang_gaffney_fisher_2021, title={Ex vivo evaluation of novel core tenorrhaphy patterns in dogs}, ISSN={["1532-950X"]}, DOI={10.1111/vsu.13678}, abstractNote={AbstractObjectiveTo compare the biomechanical properties and gapping characteristics of four novel tenorrhaphy patterns in a canine flexor tendon model.Study DesignEx vivo, randomized, biomechanical study.Sample PopulationSuperficial digital flexor tendons of 60 forelimbs (30 dogs).MethodsEach tendon was transected 25 mm distal to its musculotendinous junction prior to tenorrhaphy with 2‐0 polypropylene. Repair patterns included the three‐loop pulley (3LP, control), exposed double‐cross‐lock (ExDCrL), embedded double‐cross‐lock (EmDCrL), triple‐circle‐lock (TCiL), and Modified‐Tang patterns (MTang) were randomly assigned to each experimental group (n = 12/group). Yield, peak, and failure loads, gap formation and failure modes were compared.ResultsTendons repaired with ExDCrL (p < .0001), EmDCrL (p < .0001), and MTang (p < .0001) sustained yield, peak, and failure loads ~2.2x, ~2.0x, and ~1.9x, respectively, greater than those repaired with 3LP. Loads to 1 and 3 mm gapping were also higher for ExDCrL (p < .0001), EmDCrL (p < .0004), and MTang constructs (p < .0017) compared to 3LP. Although TCiL constructs sustained higher loads, their resistance to gap formation did not differ from that of 3LP repairs. Failure mode differed between groups (p < .0001), EmDCrL, ExDCrL, MTang, and TCiL constructs failing predominantly by suture breakage compared to 3LP repairs that failed by suture pull‐through.ConclusionUse of novel patterns ExDCrL, EmDCrL, and MTang improved resistance to loads and gap formation and were biomechanically superior compared to 3LP in healthy canine tendon repairs.Clinical SignificanceThese results justify in vivo evaluation of ExDCrL, EmDCrL, or MTang pattern for tenorrhaphy in dogs.}, journal={VETERINARY SURGERY}, author={Chiu, King Wa and Duffy, Daniel J. and Chang, Yi-Jen and Gaffney, Lewis and Fisher, Matthew B.}, year={2021}, month={Jul} }
 @article{gaffney_davis_mora-navarro_fisher_freytes_2021, title={Extracellular Matrix Hydrogels Promote Expression of Muscle-Tendon Junction Proteins}, volume={11}, ISSN={["1937-335X"]}, DOI={10.1089/ten.tea.2021.0070}, abstractNote={Muscle and tendon injuries are prevalent and range from minor sprains and strains to traumatic, debilitating injuries. However, the interactions between these tissues during injury and recovery remain unclear. Three-dimensional tissue models that incorporate both tissues and a physiologically relevant junction between muscle and tendon may help understand how the two tissues interact. Here, we use tissue specific extracellular matrix (ECM) derived from muscle and tendon to determine how cells of each tissue interact with the microenvironment of the opposite tissue, resulting in junction-specific features. The ECM materials were derived from the Achilles tendon and gastrocnemius muscle, decellularized, and processed to form tissue-specific pre-hydrogel digests. The ECM materials were unique in respect to protein composition and included many types of ECM proteins, not just collagens. After digestion and gelation, ECM hydrogels had similar complex viscosities that were less than type I collagen hydrogels at the same concentration. C2C12 myoblasts and tendon fibroblasts were cultured in tissue-specific ECM conditioned media or encapsulated in tissue-specific ECM hydrogels to determine cell–matrix interactions and the effects on a muscle–tendon junction marker, paxillin. The ECM conditioned media had only a minor effect on the upregulation of paxillin in cells cultured in monolayer. However, cells cultured within ECM hydrogels had 50–70% higher paxillin expression than cells cultured in type I collagen hydrogels. Contraction of the ECM hydrogels varied by the type of ECM used. Subsequent experiments with a varying density of type I collagen (and thus contraction) showed no correlation between paxillin expression and the amount of gel contraction, suggesting that a constituent of the ECM was the driver of paxillin expression in the ECM hydrogels. In addition, another junction marker, type XXII collagen, had similar expression patterns as paxillin, with smaller effect sizes. Using tissue-specific ECM allowed for the de-construction of the cell–matrix interactions similar to muscle–tendon junctions to study the expression of myotendinous junction-specific proteins. The muscle–tendon junction is an important feature of muscle–tendon units; however, despite crosstalk between the two tissue types, the junction is often overlooked in current research. Deconstructing the cell–matrix interactions will provide the opportunity to study significant junction-specific features and markers that should be included in tissue models of the muscle–tendon unit, while gaining a deeper understanding of the natural junction. This research aims at informing future methods to engineer a more relevant multi-tissue platform to study the muscle–tendon unit.}, journal={TISSUE ENGINEERING PART A}, author={Gaffney, Lewis S. and Davis, Zachary G. and Mora-Navarro, Camilo and Fisher, Matthew B. and Freytes, Donald O.}, year={2021}, month={Nov} }
 @article{duffy_curcillo_chang_gaffney_fisher_moore_2020, title={Biomechanical evaluation of an autologous flexor digitorum lateralis graft to augment the surgical repair of gastrocnemius tendon laceration in a canine ex vivo model}, volume={49}, ISSN={["1532-950X"]}, DOI={10.1111/vsu.13453}, abstractNote={AbstractObjectiveTo evaluate the effect of an autologous flexor digitorum lateralis (FDL) graft to augment a three‐loop pulley (3LP) core repair in a canine cadaveric gastrocnemius tendon (GT) laceration model.Study designEx vivo, biomechanical study.Sample populationTwenty‐six canine cadaveric hind limbs.MethodsTendons were divided into two groups (n = 13). After sharp transection, paired GT were repaired with 3LP or 3LP + FDL tendon augmentation. Yield, peak and failure loads, tensile loads required to create 1 and 3‐mm gapping, and failure modes were analyzed. Significance was set at P < .05.ResultsYield and failure force (mean ± SD) for 3LP + FDL were 134.9 ± 44.1 N and 205.4 ± 46.4 N, respectively, which were greater than for 3LP alone (67.9 ± 12.2 N and 91.8 ± 9.9 N, respectively, P < .0001). No constructs (0%) formed 1 or 3‐mm gaps in the 3LP + FDL graft group compared with 84% and 39% for 3LP, respectively (P < .0001). Failure modes were different between groups (P < .001), with 85% of 3LP + FDL constructs failing by tissue rupture at the myotendinous junction, distant to the repair site.ConclusionAddition of an autologous FDL graft to a core 3LP tendon repair increased yield, peak, and failure forces by twofold, 2.3‐fold, and 2.2‐fold, respectively, compared with core 3LP alone while preventing the occurrence of gap formation.Clinical significanceUse of FDL tendon augmentation for GT laceration may increase repair site strength and resist gap formation better than 3LP core suture use alone. Additional studies are required in vivo to determine the effect of FDL graft augmentation on clinical function.}, number={8}, journal={VETERINARY SURGERY}, author={Duffy, Daniel J. and Curcillo, Chiara P. and Chang, Yi-Jen and Gaffney, Lewis and Fisher, Matthew B. and Moore, George E.}, year={2020}, month={Dec}, pages={1545–1554} }
 @article{eby_duffy_chang_gaffney_fisher_moore_2020, title={Influence of barbed epitendinous suture combined with a core locking-loop sutures to repair experimental flexor tendon lacerations}, volume={49}, ISSN={["1532-950X"]}, DOI={10.1111/vsu.13496}, abstractNote={AbstractObjectiveTo determine the influence of barbed epitendinous sutures (ES) on the biomechanical properties and gap formation of repaired canine tendons.Study designEx vivo, experimental study.Sample populationEighty (n = 16/group) canine superficial digital flexor tendons (SDFT).MethodsAfter transection, SDFT were repaired with a locking‐loop (LL) pattern alone (group 1), an LL + smooth ES with monofilament suture (group 2), an LL + V‐loc‐ES (group 3), an LL + Quill‐ES (group 4), or an LL + Stratafix‐ES (group 5). All core LL repairs were performed with 0 USP polypropylene, and all ES were placed with 2‐0 USP equivalent. Constructs were preloaded and tested to failure. Yield, peak, and failure loads; occurrence of gap formation; and failure modes were compared.ResultsYield loads were greater for groups 2 and 5 (P < .0001). Peak and failure loads were greater when an ES was used (P < .005), especially for groups 2 and 5 (P < .0001). Groups with an ES required higher loads to generate 1‐ and 3‐mm gaps compared with specimens without an ES (P < .002). Force to create 1‐ and 3‐mm gaps was greater for group 5 (P < .0001) and groups 2 and 5 (P < .0001), respectively. Failure mechanism did not differ (P = .092) between ES groups, consisting of suture breakage in 51 of 64 constructs compared with pull‐through in seven of 16 group 1 constructs.ConclusionEpitendinous suture placement improved the biomechanical properties of repaired tendons. Stratafix barbed suture performed better as an ES compared with other barbed sutures and similarly to monofilament suture.Clinical significanceStratafix barbed suture eliminates the requirement for knot tying and seems to be equivalent to smooth monofilament suture when used as an ES in this pattern.}, number={8}, journal={VETERINARY SURGERY}, author={Eby, Adam C. and Duffy, Daniel J. and Chang, Yi-Jen and Gaffney, Lewis and Fisher, Matthew B. and Moore, George E.}, year={2020}, month={Dec}, pages={1590–1599} }
 @article{day_schneible_young_pozdin_driessche_gaffney_prodromou_freytes_fourches_daniele_et al._2020, title={Photoinduced reconfiguration to control the protein-binding affinity of azobenzene-cyclized peptides}, volume={8}, ISSN={["2050-7518"]}, DOI={10.1039/d0tb01189d}, abstractNote={Light-controlled switching of cell-binding activity of fluorescently-labeled peptides for on-demand cell labeling.}, number={33}, journal={JOURNAL OF MATERIALS CHEMISTRY B}, author={Day, Kevin and Schneible, John D. and Young, Ashlyn T. and Pozdin, Vladimir A. and Driessche, George and Gaffney, Lewis A. and Prodromou, Raphael and Freytes, Donald O. and Fourches, Denis and Daniele, Michael and et al.}, year={2020}, month={Sep}, pages={7413–7427} }
 @article{duffy_chang_gaffney_fisher_moore_2019, title={Effect of bite depth of an epitendinous suture on the biomechanical strength of repaired canine flexor tendons}, volume={80}, ISSN={["1943-5681"]}, DOI={10.2460/ajvr.80.11.1043}, abstractNote={Abstract

OBJECTIVE
To determine effects of bite depth for placement of an epitendinous suture on the biomechanical strength and gap formation of repaired canine tendons.


SAMPLE
48 superficial digital flexor tendons (SDFTs) obtained from 24 canine cadavers.


PROCEDURES
Tendons were assigned to 3 groups (16 tendons/group). Each SDFT was transected and then repaired with a continuous epitendinous suture placed with a bite depth of 1, 2, or 3 mm for groups 1, 2, and 3, respectively. Specimens were loaded to failure. Failure mode, gap formation, yield force, peak force, and failure force were analyzed.


RESULTS
Yield, peak, and failure forces differed significantly between groups 1 and 3 and groups 2 and 3 but not between groups 1 and 2. Comparison of the force resisted at 1 and 3 mm of gapping revealed a significant difference between groups 1 and 3 and groups 2 and 3 but not between groups 1 and 2. Failure mode did not differ among groups; suture pull-through occurred in 43 of 48 (89.6%) specimens.


CONCLUSIONS AND CLINICAL RELEVANCE
Increasing bite depth of an epitendinous suture toward the center of the tendon substance increased repair site strength and decreased the incidence of gap formation. Repair of tendon injuries in dogs by use of an epitendinous suture with bites made deep into the tendon should result in a stronger repair, which potentially would allow loading and rehabilitation to begin sooner after surgery. Suture techniques should be investigated in vivo to determine effects on tendinous healing and blood supply before clinical implementation.
}, number={11}, journal={AMERICAN JOURNAL OF VETERINARY RESEARCH}, author={Duffy, Daniel J. and Chang, Yi-Jen and Gaffney, Lewis S. and Fisher, Matthew B. and Moore, George E.}, year={2019}, month={Nov}, pages={1043–1049} }
 @article{nandi_sproul_nellenbach_erb_gaffney_freytes_brown_2019, title={Platelet-like particles dynamically stiffen fibrin matrices and improve wound healing outcomes}, volume={7}, ISSN={2047-4830 2047-4849}, url={http://dx.doi.org/10.1039/C8BM01201F}, DOI={10.1039/c8bm01201f}, abstractNote={PLPs increase fibrin stiffness, promote cell migration, and improve healing outcomes.}, number={2}, journal={Biomaterials Science}, publisher={Royal Society of Chemistry (RSC)}, author={Nandi, Seema and Sproul, Erin P. and Nellenbach, Kimberly and Erb, Mary and Gaffney, Lewis and Freytes, Donald O. and Brown, Ashley C.}, year={2019}, pages={669–682} }
 @article{gaffney_warren_wrona_fisher_freytes_2017, title={Macrophages' role in tissue disease and regeneration}, volume={62}, journal={Macrophages: origin, functions and biointervention}, author={Gaffney, L. and Warren, P. and Wrona, E. A. and Fisher, M. B. and Freytes, D. O.}, year={2017}, pages={245–271} }
 @misc{gaffney_wrona_freytes_2018, title={Potential Synergistic Effects of Stem Cells and Extracellular Matrix Scaffolds}, volume={4}, ISSN={["2373-9878"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85045213284&partnerID=MN8TOARS}, DOI={10.1021/acsbiomaterials.7b00083}, abstractNote={In recent years, extracellular matrix (ECM)-derived biomaterials have been used as scaffolds to help regenerate diseased or damaged tissues. These biomaterials are prepared by decellularization of a tissue of interest by chemical or physical removal of the cellular components. The goal of the decellularization process is to remove cells without disturbing tissue-specific composition, growth factor content, and, in some cases, the mechanical properties. As decellularization can be achieved without significantly affecting the native architecture of the tissue or organ of interest, it provides a scaffold material with native-like composition and structure. ECM scaffolds promote constructive remodeling through several mechanisms that include chemotactic properties, growth factor release, and modulation of the immune response. Constructive remodeling by ECM scaffolds relies, in part, on the recruitment of neighboring or circulating cells to the wound site. However, this is a relatively lengthy process, and the...}, number={4}, journal={ACS BIOMATERIALS SCIENCE & ENGINEERING}, author={Gaffney, Lewis and Wrona, Emily A. and Freytes, Donald O.}, year={2018}, month={Apr}, pages={1208–1222} }