Joo Hee Choi

Massive, irreparable rotator cuff tears affect a significant patient population and often require invasive procedures such as allograft patch augmentation, superior capsule reconstruction, and muscle transfers due to the limited regenerative capacity and inability to reattach the rotator cuff to the humerus. Current surgical techniques primarily focus on mechanically reinforcing the tendon without promoting biological integration, leading to high re‐tear rates and functional limitations. This study aimed to evaluate OsTend, a biphasic osteotendinous scaffold designed to span the MIRC defect by bridging the muscle to the bone footprint. As such, OsTend is designed to be conducive to supporting tendon and bone regeneration while enabling muscle tissue ingrowth. OsTend consists of electrochemically aligned collagen threads braided into a three‐region scaffold: a proximal region for muscle integration, a midsection as a tendon regeneration template along with a polycaprolactone membrane as a suture rip‐stop, and a hydroxyapatite‐infused distal region to facilitate bone ingrowth. A total of 16 New Zealand White rabbits underwent unilateral infraspinatus tendon resection and repair with OsTend, followed by biomechanical testing, micro‐computed tomography, and histological analysis at 1 and 3 months postimplantation. Results demonstrated a 65% increase in ultimate tensile strength from 1 month (102.1 ± 21.5 N) to 3 months (167.9 ± 62.3 N). Tendon retraction between 1 month (7.47 ± 2.61 mm) and 3 months (6.77 ± 1.91 mm) was < 2 mm during the study period. Bone volume fraction at 1 month (24.80% ± 8.30%) and 3 months (21.52% ± 4.97%) of the footprint reached approximately 75% of the intact bone (30%). Between 1 and 3 months, the failure mode of repaired shoulders shifted from pullout at the enthesis (80% at 1 month) to rupture at the mid‐substance (100% at 3 months), indicating attainment of a functional integration between bone and scaffold over time. Histological analysis revealed collagen fiber alignment in the muscle and tendon regions and bone‐like tissue formation surrounding the hydroxyapatite‐infused region. These findings suggest that OsTend reestablishes tendon–bone attachment with structural integrity; thus, this multiphasic biotextile platform holds the potential as an off‐the‐shelf biomaterial for treating massive irreparable rotator cuff tears.

Tendon injuries remain a major clinical challenge due to the tissue's limited regenerative capacity and poor remodeling of current allograft‐based therapies. To address these limitations, we developed a tendon‐derived thread (TDT) scaffold by electrocompacting decellularized tendon powder into aligned threads, which were subsequently woven into a porous overlay patch. Biochemical analyses of TDT confirmed efficient decellularization (DNA < 50 ng/mg) and the preservation of collagen and proteoglycans. Compared to en bloc human tendon graft (HTG), the TDT scaffold exhibited significantly higher swelling ratios and greater weight loss over 8 weeks in vitro, indicating greater porosity and faster degradation. In a rabbit infraspinatus partial‐thickness fenestration injury model, the TDT scaffold and HTG were sutured over the injury and evaluated at 2 and 8 weeks to observe tissue infiltration and in vivo response to biomaterial degradation during early phases of healing. Biomechanical testing of shoulders showed no significant differences in load relaxation, ultimate tensile strength, and stiffness among intact, HTG, and TDT scaffold groups in this injury model, suggesting comparable mechanical restoration. Histological and gross observations indicated progressive resorption of TDT scaffolds, which were infiltrated by cells at 2 weeks, and neotissue formation was evident by 8 weeks. In contrast, cell infiltration into the allograft was limited at both time points, and there was no evidence of degradation in vivo. These findings support the potential of the TDT scaffold as a degradable scaffold to support tendon healing during injury.

Repair of tendon tissues remains a complex problem in orthopedic surgery. Tendon auto‐ and allografts are not utilized to the full extent of their capabilities due largely to the lack of porosity and availability of properly processed tendon stock. Cryomilling is often utilized to maximize surface area‐to‐volume while limiting alterations to native protein/gene structure. In this study, native tendons were isolated, cryomilled, and decellularized using a truncated protocol. The resulting decellularized tendon powder exhibited reduced DNA content of less than 15 ng/mg, indicating effective removal of cellular components. The resulting decellularized tendon “powder” was then subjected to mild acidic conditions to partially solubilize the collagen within the extracellular matrix to produce a solution that could be electrochemically compacted to generate aligned fibers. Proteomic analyses revealed the presence of tendon‐related proteins (cartilage oligomeric protein, fibromodulin, lumican, biglycan, and tenascin c). Proteoglycans were present in tendon‐derived thread (TDT) and largely absent in pure collagen threads, as visualized by safranin O and quantified by dimethylmethylene blue staining. Mesenchymal stem cells seeded and cultured for up to 14 days on collagen threads and TDTs exhibited similar expression of genes related to tendon tissue.

This is the first study to provide a detailed mechanistic comparison of omecamtiv mecarbil (OM) and danicamtiv (DN) in failing and nonfailing human myocardium. These findings have clinical implications and the potential to inform the clinical utility of myosin activators in the heart failure setting.

Background: Omecamtiv mecarbil (OM) and danicamtiv both increase myocardial force output by selectively activating myosin within the cardiac sarcomere. Enhanced force generation is presumably due to an increase in the total number of myosin heads bound to the actin filament; however, detailed comparisons of the molecular mechanisms of OM and danicamtiv are lacking. Methods and Results: The effect of OM and danicamtiv on Ca ²⁺ sensitivity of force generation was analyzed by exposing chemically skinned myocardial samples to a series of increasing Ca ²⁺ solutions. The results showed that OM significantly increased Ca ²⁺ sensitivity of force generation, whereas danicamtiv showed similar Ca ²⁺ sensitivity of force generation to untreated preparations. A direct comparison of OM and danicamtiv on dynamic cross‐bridge behavior was performed at a concentration that produced a similar force increase when normalized to predrug levels at submaximal force (pCa 6.1). Both OM and danicamtiv‐treated groups slowed the rates of cross‐bridge detachment from the strongly bound state and cross‐bridge recruitment into the force‐producing state. Notably, the significant OM‐induced prolongation in the time to reach force relaxation and subsequent commencement of force generation following rapid stretch was dramatically reduced in danicamtiv‐treated myocardium. Conclusions: This is the first study to directly compare the effects of OM and danicamtiv on cross‐bridge kinetics. At a similar level of force enhancement, danicamtiv had a less pronounced effect on the slowing of cross‐bridge kinetics and, therefore, may provide a similar improvement in systolic function as OM without excessively prolonging systolic ejection time and slowing cardiac relaxation facilitating diastolic filling at the whole‐organ level.

Hydrogel is a versatile material that can be manipulated to achieve the desired physicochemical properties, such as stiffness, pore size, and viscoelasticity. Traditionally, these properties have been controlled through parameters such as concentration and pH adjustments. In this study, we focused on exploring the potential of hydrolyzed silk fibroin (HSF) as a molecular weight-modulating agent to control the physicochemical properties of double-composite hydrogels. We developed a synergistic dual-crosslinked hydrogel by combining ionically crosslinked silk fibroin with gellan gum (GG). The hydrolysis of silk fibroin not only enhanced its hydrophilicity but also enabled adjustments in its mechanical properties, including the pore size, initial modulus elasticity, and relaxation time. Moreover, biocompatibility assessments based on cell viability tests confirmed the potential of these hydrogels as biocompatible materials. By highlighting the significance of developing an HSF/GG dual-crosslinked hydrogel, this study contributes to the advancement of novel double-composite hydrogels with remarkable biocompatibility. Overall, our findings demonstrate the capability of controlling the mechanical properties of hydrogels through molecular weight modulation via hydrolysis and highlight the development of a biocompatible HSF/GG dual-crosslinked hydrogel with potential biomedical applications.

Cardiac myosin binding protein C (cMyBPC) is an 11-domain sarcomeric protein (C0–C10) integral to cardiac muscle regulation. In vitro studies have demonstrated potential functional roles for regions beyond the N-terminus. However, the in vivo contributions of these domains are mostly unknown. Therefore, we examined the in vivo consequences of expression of N-terminal truncated cMyBPC (C3C10). Neonatal cMyBPC^−/− mice were injected with AAV9-full length (FL), C3C10 cMyBPC, or saline, and echocardiography was performed 6 wk after injection. We then isolated skinned myocardium from virus-treated hearts and performed mechanical experiments. Our results show that expression of C3C10 cMyBPC in cMyBPC^−/− mice resulted in a 28% increase in systolic ejection fraction compared to saline-injected cMyBPC^−/− mice and a 25% decrease in left ventricle mass-to-body weight ratio. However, unlike expression of FL cMyBPC, there was no prolongation of ejection time compared to saline-injected mice. In vitro mechanical experiments demonstrated that functional improvements in cMyBPC^−/− mice expressing C3C10 were primarily due to a 35% reduction in the rate of cross-bridge recruitment at submaximal Ca²⁺ concentrations when compared to hearts from saline-injected cMyBPC^−/− mice. However, unlike the expression of FL cMyBPC, there was no change in the rate of cross-bridge detachment when compared to saline-injected mice. Our data demonstrate that regions of cMyBPC beyond the N-terminus are important for in vivo cardiac function, and have divergent effects on cross-bridge behavior. Elucidating the molecular mechanisms of cMyBPC region-specific function could allow for development of targeted approaches to manipulate specific aspects of cardiac contractile function.

Shape-memory polymers (SMPs) can be defined as a reversibly changing form through deformation and recovery by external stimuli. However, there remain application limitations of SMPs, such as complicated preparation processes and slow shape recovery. Here, we designed gelatin-based shape-memory scaffolds by a facile dipping method in tannic acid solution. The shape-memory effect of scaffolds was attributed to the hydrogen bond between gelatin and tannic acid, which acts as the net point. Moreover, gelatin (Gel)/oxidized gellan gum (OGG)/calcium chloride (Ca) was intended to induce faster and more stable shape-memory behavior through the introduction of a Schiff base reaction. The chemical, morphological, physicochemical, and mechanical properties of the fabricated scaffolds were evaluated, and those results showed that the Gel/OGG/Ca had improved mechanical properties and structural stability compared with other scaffold groups. Additionally, Gel/OGG/Ca exhibited excellent shape-recovery behavior of 95.8% at 37 °C. As a consequence, the proposed scaffolds can be fixed to the temporary shape at 25 °C in just 1 s and recovered to the original shape at 37 °C within 30 s, implying a great potential for minimally invasive implantation.

Cell therapies for age-related macular degeneration (AMD) treatment have been developed by integrating hydrogel-based biomaterials. Until now, cell activity has been observed only in terms of the modulus of the hydrogel. In addition, cell behavior has only been observed in the 2D environment of the hydrogel and the 3D matrix. As time-dependent stress relaxation is considered a significant mechanical cue for the control of cellular activities, it is important to optimize hydrogels for retinal tissue engineering (TE) by applying this viewpoint. Herein, a gellan Gum (GG)/Hyaluronic acid (HA) hydrogel was fabricated using a facile physical crosslinking method. The physicochemical and mechanical properties were controlled by forming a different composition of GG and HA. The characterization was performed by conducting a mass swelling study, a sol fraction study, a weight loss test, a viscosity test, an injection force study, a compression test, and a stress relaxation analysis. The biological activity of the cells encapsulated in 3D constructs was evaluated by conducting a morphological study, a proliferation test, a live/dead analysis, histology, immunofluorescence staining, and a gene expression study to determine the most appropriate material for retinal TE biomaterial. Hydrogels with moderate amounts of HA showed improved physicochemical and mechanical properties suitable for injection into the retina. Moreover, the time-dependent stress relaxation property of the GG/HA hydrogel was enhanced when the appropriate amount of HA was loaded. In addition, the cellular compatibility of the GG/HA hydrogel in in vitro experiments was significantly improved in the fast-relaxing hydrogel. Overall, these results demonstrate the remarkable potential of GG/HA hydrogel as an injectable hydrogel for retinal TE and the importance of the stress relaxation property when designing retinal TE hydrogels. Therefore, we believe that GG/HA hydrogel is a prospective candidate for retinal TE biomaterial.