Injectable FHE+BP composites hydrogel with enhanced regenerative capacity of tendon-bone interface for anterior cruciate ligament reconstruction.

Features of black phosphorous (BP) nano sheets such as enhancing mineralization and reducing cytotoxicity in bone regeneration field have been reported. Thermo-responsive FHE hydrogel (mainly composed of oxidized hyaluronic acid (OHA), poly-ε-L-lysine (ε-EPL) and F127) also showed a desired outcome in skin regeneration due to its stability and antibacterial benefits. This study investigated the application of BP-FHE hydrogel in anterior cruciate ligament reconstruction (ACLR) both in in vitro and in vivo, and addressed its effects on tendon and bone healing. This BP-FHE hydrogel is expected to bring the benefits of both components (thermo-sensitivity, induced osteogenesis and easy delivery) to optimize the clinical application of ACLR and enhance the recovery. Our in vitro results confirmed the potential role of BP-FHE via significantly increased rBMSC attachment, proliferation and osteogenic differentiation with ARS and PCR analysis. Moreover, In vivo results indicated that BP-FHE hydrogels can successfully optimize the recovery of ACLR through enhancing osteogenesis and improving the integration of tendon and bone interface. Further results of Biomechanical testing and Micro-CT analysis [bone tunnel area (mm2) and bone volume/total volume (%)] demonstrated that BP can indeed accelerate bone ingrowth. Additionally, histological staining (H&E, Masson and Safranin O/fast green) and immunohistochemical analysis (COL I, COL III and BMP-2) strongly supported the ability of BP to promote tendon-bone healing after ACLR in murine animal models.

Exosomes Derived From Kartogenin-Preconditioned Mesenchymal Stem Cells Promote Cartilage Formation and Collagen Maturation for Enthesis Regeneration in a Rat Model of Chronic Rotator Cuff Tear.

BACKGROUND: Poor tendon-to-bone healing in chronic rotator cuff tears (RCTs) is related to unsatisfactory outcomes. Exosomes derived from mesenchymal stem cells reportedly enhance rotator cuff healing. However, the difficulty in producing exosomes with a stronger effect on enthesis regeneration must be resolved. PURPOSE: To study the effect of exosomes derived from kartogenin (KGN)-preconditioned human bone marrow mesenchymal stem cells (KGN-Exos) on tendon-to-bone healing in a rat model of chronic RCT. STUDY DESIGN: Controlled laboratory study. METHODS: Exosome-loaded sodium alginate hydrogel (SAH) was prepared. Moreover, exosomes were labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) or 1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate (Dil) for in vivo tracking. Bilateral rotator cuff repair (RCR) was conducted in an established chronic RCT rat model. A total of 66 rats were randomized to control, untreated exosome (un-Exos), and KGN-Exos groups to receive local injections of pure SAH, un-Exos, or KGN-Exos SAH at the repaired site. The presence of DiR/Dil-labeled exosomes was assessed at 1 day and 1 week, and tendon-to-bone healing was evaluated histologically, immunohistochemically, and biomechanically at 4 and 8 weeks. RESULTS: Both un-Exos and KGN-Exos exhibited sustained release from SAH for up to 96 hours. In vivo study revealed that un-Exos and KGN-Exos were localized to the repaired site at 1 week. Moreover, the KGN-Exos group showed a higher histological score and increased glycosaminoglycan and collagen II expression at 4 and 8 weeks. In addition, more mature and better-organized collagen fibers with higher ratios of collagen I to collagen III were observed at 8 weeks in the tendon-to-bone interface compared with those in the control and un-Exos groups. Biomechanically, the KGN-Exos group had the highest failure load (28.12 ± 2.40 N) and stiffness (28.57 ± 2.49 N/mm) among the 3 groups at 8 weeks. CONCLUSION: Local injection of SAH with sustained KGN-Exos release could effectively promote cartilage formation as well as collagen maturation and organization for enthesis regeneration, contributing to enhanced biomechanical properties after RCR. CLINICAL RELEVANCE: KGN-Exos injection may be used as a cell-free therapeutic option to accelerate tendon-to-bone healing in chronic RCT.

Constructing high-strength nano-micro fibrous woven scaffolds with native-like anisotropic structure and immunoregulatory function for tendon repair and regeneration.

Tendon injuries are common debilitating musculoskeletal diseases with high treatment expenditure in sports medicine. The development of tendon-biomimetic scaffolds may be promising for improving the unsatisfactory clinical outcomes of traditional therapies. In this study, we combined an advanced electrospun nanofiber yarn-generating technique with a traditional textile manufacturing strategy to fabricate innovative nano-micro fibrous woven scaffolds with tendon-like anisotropic structure and high-strength mechanical properties for the treatment of large-size tendon injury. Electrospun nanofiber yarns made from pure poly L-lactic acid (PLLA) or silk fibroin (SF)/PLLA blend were fabricated, and their mechanical properties matched and even exceeded those of commercial PLLA microfiber yarns. The PLLA or SF/PLLA nanofiber yarns were then employed as weft yarns interlaced with commercial PLLA microfiber yarns as warp yarns to generate two new types of nanofibrous scaffolds (nmPLLA and nmSF/PLLA) with a plain-weaving structure. Woven scaffolds made from pure PLLA microfiber yarns (both weft and warp directions) (mmPLLA) were used as controls.In vitroexperiments showed that the nmSF/PLLA woven scaffold with aligned fibrous topography significantly promoted cell adhesion, elongation, proliferation, and phenotypic maintenance of tenocytes compared with mmPLLA and nmPLLA woven scaffolds. Moreover, the nmSF/PLLA woven scaffold exhibited the strongest immunoregulatory functions and effectively modulated macrophages towards the M2 phenotype.In vivoexperiments revealed that the nmSF/PLLA woven scaffold notably facilitated Achilles tendon regeneration with improved structure by macroscopic, histological, and ultrastructural observations six months after surgery, compared with the other two groups. More importantly, the regenerated tissue in the nmSF/PLLA group had excellent biomechanical properties comparable to those of the native tendon. Overall, our study provides an innovative biological-free strategy with ready-to-use features, which presents great potential for clinical translation for damaged tendon repair.

Corrigendum: Advances in regenerative sports medicine research.

[This corrects the article DOI: 10.3389/fbioe.2022.908751.].

Glenoid Bone Loss Determination: Validity and Reliability of the Constellation Technique Versus the Sagittal Best Fit Circle Technique.

Objective: To propose a new method for glenoid bone loss measurement, the constellation technique (CST); determine its reliability and accuracy; and compare the validity of CST with that of the conventional technique (CVT) and standard measurements for ratio calculation. Materials and Methods: Sixty shoulders with intact glenoids and no glenohumeral instability and arthritis underwent CT scans. Simulated osteotomies were conducted on the 3D models of glenoids at two cutting locations, expressed as clock face times (2:30-4:20; 1:30-5:00). Two experienced surgeons compared three methods for glenoid bone loss measurement; CVT (best-fit circle), CST ('5S' steps), and standard measurement. Eight undergraduates remeasured five randomly chosen shoulders with moderate to severe bone loss. Intraclass correlation coefficients (ICCs) were calculated for raters. Results: With a defect range between 2:30 and 4:20, all 60 glenoids demonstrated minimal bone loss (< 15%); while between 1:30 and 5:00, 42 shoulders were with moderate bone loss (15-20%), and 18 shoulders with severe bone loss (≥ 20%). For experienced raters, no significant differences were noted between protocos for all categories of bone loss (p ≥ 0.051), with good inter- and intraobserver reliability indicated by ICC. For novice raters, post hoc Tukey analysis found that CST was more accurate in one patient with a standard mean bone loss of 23.2% ± 1.9% compared with CVT. Conclusion: The CST turned the key step of glenoid defect evaluation from deciding an en face view to determining the glenoid inferior rim. The protocol is simple, accurate, and reproducible, especially for novice raters.

Advances in Regenerative Sports Medicine Research.

Regenerative sports medicine aims to address sports and aging-related conditions in the locomotor system using techniques that induce tissue regeneration. It also involves the treatment of meniscus and ligament injuries in the knee, Achilles' tendon ruptures, rotator cuff tears, and cartilage and bone defects in various joints, as well as the regeneration of tendon-bone and cartilage-bone interfaces. There has been considerable progress in this field in recent years, resulting in promising steps toward the development of improved treatments as well as the identification of conundrums that require further targeted research. In this review the regeneration techniques currently considered optimal for each area of regenerative sports medicine have been reviewed and the time required for feasible clinical translation has been assessed. This review also provides insights into the direction of future efforts to minimize the gap between basic research and clinical applications.

Effect of Anterolateral Structure Augmentation on Graft Maturity After Anterior Cruciate Ligament Reconstruction: A Clinical and MRI Follow-up of 2 Years.

BACKGROUND: Anterolateral structure augmentation (ALSA) has been applied to prevent residual rotatory instability and lower clinical failure rates after anterior cruciate ligament (ACL) reconstruction (ACLR); however, the effect of combined ALSA on the maturity of ACL grafts remains unknown. PURPOSE: To evaluate the graft maturity and patient-reported outcomes in patients who underwent double-bundle ACLR with or without ALSA. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 92 patients who underwent double-bundle ACLR between January 2016 and July 2019 were included in the present study-44 patients with isolated ACLR (ACLR group) and 48 patients with combined ACLR and ALSA (ALSA group). Demographic characteristics, intraoperative findings, and patient-reported outcomes were prospectively collected. On postoperative magnetic resonance imaging at the 2-year follow-up, the signal-to-noise quotient (SNQ) values were separately calculated for 6 sections of the ACL graft, including the femoral intratunnel graft (FTG), intra-articular graft (IAG), and tibial intratunnel graft (TTG) of the anteromedial bundle (AMB) and the posterolateral bundle (PLB). Superior graft maturity was usually indicated by lower SNQ values. RESULTS: The rates of return to preinjury sports were 47.9% and 27.3% in the ALSA and ACLR groups, respectively (difference, 20.6% [95% CI, 1.3%-40%]; P = .042). The AMB demonstrated significantly lower SNQ values in the ALSA group than in the ACLR group (FTG, 7.04 ± 3.65 vs 9.44 ± 4.51 [P = .006]; IAG, 6.62 ± 4.19 vs 8.77 ± 5.92 [P = .046]; TTG, 6.93 ± 3.82 vs 8.75 ± 4.55 [P = .040]). The SNQ values were significantly lower in the ALSA group for 2 of the 3 sections of the PLB (IAG, 7.73 ± 4.61 vs 9.88 ± 5.61 [P = .047]; TTG, 5.88 ± 3.10 vs 8.57 ± 4.32 [P = .001]). Partial lateral meniscectomy was correlated with higher SNQ values of the TTG in the AMB (ß = 0.27; P = .009) and the PLB (ß = 0.25; P = .008), with both groups pooled. Higher body mass index, smaller ACL graft-Blumensaat line angles, larger AMB graft diameters, and lower postoperative Tegner scores were also associated with inferior maturity in specific regions of the ACL graft. CONCLUSION: A combination of ACLR and ALSA is a desirable option to improve the maturity of ACL grafts for patients who are young or expected to return to pivoting sports. Meanwhile, further investigations with higher levels of evidence and longer periods of follow-up are warranted.

Abaloparatide Improves Rotator Cuff Healing via Anabolic Effects on Bone Remodeling in a Chronic Rotator Cuff Tear Model of Rat With Osteoporosis: A Comparison With Denosumab.

BACKGROUND: Because of poor clinical outcomes, rotator cuff healing in patients with osteoporosis has recently gained attention. Antiresorptive therapy for osteoporosis has been reported to improve healing after repair. However, the comparative effectiveness of anabolic and antiresorptive agents has not been investigated. HYPOTHESIS: Anabolic therapy with abaloparatide (ABL) would outperform antiresorptive therapy with denosumab (Dmab) to improve rotator cuff healing in the osteoporotic status. STUDY DESIGN: Controlled laboratory study. METHODS: A chronic rotator cuff tear model was established in ovariectomy-induced postmenopausal osteoporotic rats. Then, bilateral rotator cuff repairs were conducted in all experimental rats, which were randomly divided into control (CON), Dmab, and ABL groups to receive the corresponding subcutaneous injections. The rats sacrificed at 2 weeks (the early healing period) were used to detect osteoblast and osteoclast activities, related gene expression (osteoclastogenesis, osteogenesis, and chondrogenesis), new bone formation, and mineralization. In the rats sacrificed at 4 and 8 weeks, the bone mineral density and bone architecture at the repaired site were assessed by micro-computed tomography, and rotator cuff healing was evaluated using histological and biomechanical analyses. RESULTS: At 8 weeks, significantly higher failure load and stiffness were observed in the ABL (25.13 ± 3.54 N, P < .001; 21.65 ± 3.08 N/mm, P < .001; respectively), and Dmab (21.21 ± 2.55 N, P < .001; 16.15 ± 2.07 N/mm, P = .008; respectively) groups than in the CON group (13.36 ± 1.70 N; 11.20 ± 2.59 N/mm; respectively), whereas the ABL treatment provided better failure load and stiffness than Dmab (P = .019; P = .003). Although tendon-to-bone healing was improved by Dmab, the most mature tendon insertion at the interface was observed in the ABL group, including a more organized collagen and fibrocartilage and higher bone quality. ABL significantly promoted bone remodeling via coupling between osteoclasts and osteoblasts (osteoblast to osteoclast ratio: 4.80 ± 0.39; P = .022), thereby stimulating more new bone formation and mineralization at the tendon-to-bone healing interface than Dmab (osteoblast to osteoclast ratio: 3.21 ± 0.75) at 2 weeks. Moreover, ABL had significant effects on gene expression [Runt-realted transcription factor 2 (Runx2, collagen type I-alpha 1 (Col1A1]), and sclerostin for osteogenesis; aggrecan and collagen type II (Col2) for chondrogenesis] in mineralized tissues, indicative of enhanced bone and fibrocartilage formation when compared with the CON and Dmab groups. CONCLUSION: ABL promoted rotator cuff healing in osteoporotic rats by significantly increasing the mineralized tissue quality and collagen maturity at the reattachment site, leading to improved biomechanical properties, and was superior to Dmab in both biomechanical and histological analyses. CLINICAL RELEVANCE: Anabolic therapy with ABL may outperform antiresorptive therapy with Dmab in improving outcomes after rotator cuff repair in osteoporotic patients.

A regeneration process-matching scaffold with appropriate dynamic mechanical properties and spatial adaptability for ligament reconstruction.

Ligament regeneration is a complicated process that requires dynamic mechanical properties and allowable space to regulate collagen remodeling. Poor strength and limited space of currently available grafts hinder tissue regeneration, yielding a disappointing success rate in ligament reconstruction. Matching the scaffold retreat rate with the mechanical and spatial properties of the regeneration process remains challenging. Herein, a scaffold matching the regeneration process was designed via regulating the trajectories of fibers with different degradation rates to provide dynamic mechanical properties and spatial adaptability for collagen infiltration. This core-shell structured scaffold exhibited biomimetic fiber orientation, having tri-phasic mechanical behavior and excellent strength. Besides, by the sequential material degradation, the available space of the scaffold increased from day 6 and remained stable on day 24, consistent with the proliferation and deposition phase of the native ligament regeneration process. Furthermore, mature collagen infiltration and increased bone integration in vivo confirmed the promotion of tissue regeneration by the adaptive space, maintaining an excellent failure load of 67.65% of the native ligament at 16 weeks. This study proved the synergistic effects of dynamic strength and adaptive space. The scaffold matching the regeneration process is expected to open new approaches in ligament reconstruction.

Infrapatellar Fat Pad Mesenchymal Stromal Cell-Derived Exosomes Accelerate Tendon-Bone Healing and Intra-articular Graft Remodeling After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Exosomes derived from mesenchymal stromal cells (MSCs) reportedly enhance the healing process. However, no studies have investigated the effect of exosomes from infrapatellar fat pad (IPFP) MSCs on tendon-bone healing and intra-articular graft remodeling after anterior cruciate ligament reconstruction (ACLR). PURPOSE: To evaluate the in vivo effect of exosomes from IPFP MSCs on tendon-bone healing and intra-articular graft remodeling in a rat model of ACLR. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 90 skeletally mature male Sprague Dawley rats underwent unilateral ACLR using an autograft. All rats were randomly divided into 3 groups: sham injection (SI) group (n = 30), control injection (CI) group (n = 30), and IPFP MSC-derived exosome injection (IMEI) group (n = 30). At 2, 4, and 8 weeks postoperatively, tendon-bone healing and intra-articular graft remodeling were evaluated via biomechanical testing, micro-computed tomography, and histological analysis; macrophage polarization was evaluated using immunohistochemical staining. RESULTS: Biomechanical testing demonstrated a significantly higher failure load and stiffness in the IMEI group than in the SI and CI groups at 4 and 8 weeks postoperatively. Moreover, a thinner graft-to-bone healing interface with more fibrocartilage was observed in the IMEI group at both time points. Micro-computed tomography revealed greater new bone ingrowth in the IMEI group than in the other groups, as demonstrated by smaller mean bone tunnel areas and a larger bone volume/total volume ratio. Additionally, more cellular infiltration was observed in the intra-articular graft in the IMEI group than in the other groups at 4 weeks, followed by more regularly organized fibers with mature collagen at 8 weeks. Notably, similar trends of macrophage polarization were found at both the graft-to-bone interface and the intra-articular graft in the IMEI group, with significantly fewer proinflammatory M1 macrophages and larger numbers of reparative M2 macrophages than in the SI and CI groups. CONCLUSION: IPFP MSC-derived exosomes accelerated tendon-bone healing and intra-articular graft remodeling after ACLR, which may have resulted from the immunomodulation of macrophage polarization. CLINICAL RELEVANCE: The IPFP can be easily harvested by most orthopaedic surgeons. Exosomes from IPFP MSCs, constituting a newly emerging cell-free approach, may represent a treatment option for improving tendon-bone healing and intra-articular graft remodeling after ACLR.

Computed Tomography Imaging Analysis of the MPFL Femoral Footprint Morphology and the Saddle Sulcus: Evaluation of 1094 Knees.

BACKGROUND: The medial patellofemoral ligament (MPFL) has been reported to be anatomically attached from an osseous saddle region (saddle sulcus) between neighboring landmarks on the femur, including the adductor tubercle (AT), medial epicondyle (ME), and medial gastrocnemius tubercle (MGT). However, the position and prevalence of the saddle sulcus remain unknown. PURPOSE: To study the femoral footprint of MPFL and the prevalence of the saddle sulcus with computed tomography (CT) imaging; quantify the position of the saddle sulcus; and determine the relevant factors of the identified position and measuring distances. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 1094 knees in 753 patients were studied. Knees were organized into an anterior cruciate ligament reconstruction (ACLR) group (controls) and a recurrent patellar dislocation (RPD) group. Using 3-dimensionally reconstructed CT images, the authors determined the prevalence of the saddle sulcus and its position relative to the AT, the ME, the Schöttle point (1.3 mm anterior to the distal posterior cortex and 2.5 mm distal to the posterior origin of the medial femoral condyle), and the Fujino point (approximately 10 mm distal to the AT). Analysis of covariance was used to adjust for age, sex, side, and body mass index on the measurements. RESULTS: There were 555 knees in the control group and 539 knees in the RPD group. The MPFL femoral footprint presented as an oblique, oblong, osseous region (saddle sulcus) in 75.7% of knees (75.0%, ACLR group vs 76.4%, RPD group; P < .001). The saddle sulcus was located a mean of 12.2 mm (95% CI, 12.0-12.4 mm) from a line connecting the apex of the AT to the ME (AT-ME) and a mean of 7.6 mm (95% CI, 7.5-7.8 mm) posteriorly perpendicular to that line. The location as a proportion of the AT-ME distance was 63.1% (95% CI, 62.6%-63.7%) in the X direction and 39.8% (95% CI, 39.1%-40.5%) in the Y direction. The Schöttle and Fujino points lay anterior and proximal to the saddle sulcus more than 5 mm away from the center of the saddle sulcus. Women had a higher prevalence of saddle sulcus (odds ratio [OR], 1.33 [95% CI, 1.00-1.75]; P = .046) compared with men. CONCLUSION: The saddle sulcus was identified in 75.7% of knees from the medial femoral aspect, with its center located consistently between the AT and ME.

Combining electrospinning with hot drawing process to fabricate high performance poly (L-lactic acid) nanofiber yarns for advanced nanostructured bio-textiles.

Fiber constructed yarns are the elementary building blocks for the generation of implantable biotextiles, and there are always needs for designing and developing new types of yarns to improve the properties of biotextile implants. In the present study, we aim to develop novel nanofiber yarns (NYs) by combining nanostructure that more closely mimic the extracellular matrix fibrils of native tissues with biodegradability, strong mechanical properties and great textile processibility. A novel electrospinning system which integrates yarn formation with hot drawing process was developed to fabricate poly(L-lactic acid) (PLLA) NYs. Compared to the PLLA NYs without hot drawing, the thermally drawn PLLA NYs presented superbly-orientated fibrous structure and notably enhanced crystallinity. Importantly, they possessed admirable mechanical performances, which matched and even exceeded the commercial PLLA microfiber yarns (MYs). The thermally drawn PLLA NYs were also demonstrated to notably promote the adhesion, alignment, proliferation, and tenogenic differentiation of human adipose derived mesenchymal stem cells (hADMSCs) compared to the PLLA NYs without hot drawing. The thermally drawn PLLA NYs were further processed into various nanofibrous tissue scaffolds with defined structures and adjustable mechanical and biological properties using textile braiding and weaving technologies, demonstrating the feasibility and versatility of thermally drawn PLLA NYs for textile-forming utilization. The hADMSCs cultured on PLLA NY-based textiles presented enhanced attachment and proliferation capacities than those cultured on PLLA MY-based textiles. This work presents a facile technique to manufacture high performance PLLA NYs, which opens up opportunities to generate advanced nanostructured biotextiles for surgical implant applications.

Acceleration of ligamentization and osseointegration processes after anterior cruciate ligament reconstruction with autologous tissue-engineered polyethylene terephthalate graft.

BACKGROUND: Despite the advantages of excellent mechanical properties for rapid return to sports and early rehabilitation after anterior cruciate ligament (ACL) reconstruction with polyethylene terephthalate (PET) artificial ligament, the graft failure rate during long-term follow-up is relatively high due to poor graft-host incorporation. The purpose of the present study was to investigate the effect of autologous tissue-engineered PET (ATE-PET) grafts on osseointegration and ligamentization after ACL reconstruction. METHODS: Forty-eight New Zealand white rabbits were randomly divided into PET group (n=24) and ATE-PET group (n=24). In the ATE-PET group, the rabbits initially underwent subcutaneous implantation of the PET ligament. Two weeks later, unilateral ipsilateral ACL reconstruction was performed using an ATE-PET graft. In the PET group, the rabbits underwent ACL reconstruction using PET grafts as controls. Macroscopic observation, micro-computed tomography, histological and immunofluorescent staining, and biomechanical tests were conducted to evaluate the effects at 4 and 12 weeks postoperatively. RESULTS: The ATE-PET graft was highly pre-vascularized with myofibroblast aggregation after two weeks of subcutaneous implantation. With regard to the intraosseous part of the graft, the ATE-PET group had significantly higher bone mineral density and bone volume/total volume ratio at 12 weeks. Histologically, the width of the interface between the graft and bone was smaller. Regarding the intra-articular part, thicker tissue coverage with a glossy appearance was observed in the ATE-PET group at 12 weeks on macroscopic observation. Histological staining also showed more collagen fibers grew in the grafts with fewer inflammatory reactions of the ATE-PET group at both 4 and 12 weeks. Immunofluorescently, both α-SMA-positive vessels and α-SMA-positive myofibroblasts were found to be significantly greater around the graft in the ATE-PET group at 4 weeks and markedly declined at 12 weeks. Moreover, the ATE-PET group presented significantly greater failure load and stiffness than the PET group at 12 weeks (53.7±5.4 vs. 42.5±4.5 N, P<0.01; 12.9±3.0 vs. 9.8±1.3 N/mm, P=0.04). CONCLUSIONS: The ATE-PET artificial ligament with pre-vascularization and myofibroblast aggregation could effectively accelerate intra-articular graft ligamentization and intraosseous graft osseointegration, thus enhancing the biomechanical properties after ACL reconstruction in a rabbit model.

Tendon-bioinspired wavy nanofibrous scaffolds provide tunable anisotropy and promote tenogenesis for tendon tissue engineering.

The development of tendon-biomimetic nanofibrous scaffolds with mesenchymal stem cells may represent a promising strategy to improve the unsatisfactory outcomes of traditional treatments in tendon repair. In the present study, the nanofibrous scaffolds comprised of poly(p-dioxanone) (PPDO) and silk fibroin (SF) composites were fabricated by using electrospinning technique and subsequent thermal ethanol treatment. The PPDO/SF composite scaffolds presented parallel fiber arrangement with crimped features and nonlinear mechanical properties, which mimic the structure-function relationship of native tendon tissue mechanics. We demonstrated that the fiber crimp degree and mechanical properties of as-prepared PPDO/SF wavy nanofibrous scaffolds (WNSs) could be tunable by adjusting the mass ratio of PPDO/SF. The biological tests revealed that the addition of SF obviously promoted the cell adhesion, proliferation, and phenotypic maintenance of human tenocytes on the WNSs. A preliminary study on the subcutaneous implantation showed that the PPDO/SF WNSs notably decreased the inflammatory response compared with pure PPDO WNSs. More importantly, a combination of growth factor induction and mechanical stimulation was found to notably enhance the tenogenic differentiation of human adipose derived mesenchymal stem cells on the PPDO/SF WNSs by upregulating the expressions of tendon-associated protein and gene markers. Overall, this study demonstrated that our PPDO/SF WNSs could provide a beneficial microenvironment for various cell activities, making them an attractive candidate for tendon tissue engineering research.

Establishment of near and non isometric anterior cruciate ligament reconstruction with artificial ligament in a rabbit model.

BACKGROUND: Tunnel position deicide the isometry of graft attachment in synthetic anterior cruciate ligament (ACL) reconstruction. Near-isometric tunnel position may have advantage in graft integration and knee function in ACL reconstruction (ACLR) with polyethylene terephthalate (PET) ligament. Few studies focused on tunnel position isometry when conduct ACLR with an animal model. This study aimed to establish a preclinical rabbit model of near and non isometric ACLR with PET ligament and investigate the advantage of near-isometric ACLR compared to non-isometric ACLR. METHODS: Nine hind limbs of rabbit were used in tunnel position study. Two femoral(anatomic, nonanatomic) tunnels and three tibial(anterior, middle, posterior) tunnels were used to measure tunnel position isometry during knee full range of motion. The tunnel position combination with minimal isometry was considered as near-isometric tunnel position. Then, 48 rabbits divided into two groups were conducted near or non isometric ACLR with PET ligament with graft fixation angle of 30° and constant tension of 5N. PET ligament isometry, range of motion(ROM) restriction, knee laxity were recorded after operation and followed up with macroscopic observation, microcomputed tomography (micro-CT) analysis, histology assessment and biomechanical test at 4 and 8 weeks postoperatively. RESULTS: The tunnel combination with minimal isometry was femoral anatomic position and tibial posterior position(5.19 â€‹± â€‹1.78%) and considered as near-isometric tunnel position. ROM restriction were observed in non-isometric group (22.50 â€‹± â€‹14.14°) while none in near-isometric group. However, no ROM restriction observed at 8 weeks in both group. Knee laxity compared to contralateral knee were better in near-isometric group than non-isometric group (stable/slack/total 10/2/12 VS 3/9/12, p â€‹= â€‹0.012) at 8 weeks postoperatively. Supeiror PET ligament integration were also observed in near-isometric group through macroscopic observation, micro-CT analysis, histology assessment at both 4 and 8 weeks. The failure load in the Near-Isometric group at 8 weeks were higher than timezero reconstruction with statistical difference (156.8N â€‹± â€‹25.98N vs.102.6 â€‹± â€‹22.96N, p â€‹= â€‹0.02). CONCLUSION: A rabbit model of ACLR based on tunnel position isometry was successfully established in this study. The near-isometric tunnel position in rabbit model was femoral anatomic position and tibial posterior position. A near-isometric ACLR with PET ligament did not cause ROM restriction and had a better graft integration and follow-up stability than non-isometric ACLR with ROM restriction. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The study demonstrate the establishmentof near-isometric tunnel position and non-isometric tunnel position with significant difference of ROM restriction and graft-bone integration. The described tunnel positions with differential isometry in a rabbit ACLR provides a reproducible and translational small animal model and enables preclinical research between tunnel position isometry and its affection on variable grafts, graft integration and knee function.

An interference screw made using a silk fibroin-based bulk material with high content of hydroxyapatite for anterior cruciate ligament reconstruction in a rabbit model.

Upgradation is still in need for the clinically applied interference screws in anterior cruciate ligament reconstruction for more reliable fixation. Silk fibroin bulk materials offer a promising opportunity for this application except lacking osteoinductivity to some extent. Here we report a novel silk-based bulk material with high content of hydroxyapatite-silk fibroin (HA-SF) hybrid particles, which is prepared via a dual-network hydrogel. This composite bulk material possesses a compression modulus of 3.2 GPa, comparable to that of the natural compact bone, and presents satisfactory cytocompatibility and osteoinductivity in vitro when combined with the HA-SF nanoparticles particularly. This composite bulk material shaped into interference screws exhibits remarkable biomechanical properties and significant new-bone ingrowth in the host bone tunnel in a rabbit anterior cruciate ligament reconstruction (ACLR) model at 4 weeks and 12 weeks post-operatively. Moreover, considering that this "hydrogel method" allows the material to be formed in a mold, avoiding complicated post fabrication, it is a potential candidate for clinical translation.

The Effect of Antiosteoporosis Therapy With Risedronate on Rotator Cuff Healing in an Osteoporotic Rat Model.

BACKGROUND: Osteoporosis increases the revision rate of rotator cuff repair (RCR). Weak fixation might not be the only cause of high RCR failure rates. The biological mechanism associated with tendon-to-bone healing after RCR in osteoporosis should be investigated. HYPOTHESIS: (1) Osteoporosis would impair rotator cuff healing through the high osteoclastic activity at the repaired interface. (2) Risedronate would promote rotator cuff healing by reducing osteoclastic activity at the repaired interface. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 84 female Sprague Dawley rats were randomly treated using ovariectomy or sham surgeries to establish osteoporotic and nonosteoporotic rat models. After confirming osteoporosis, a chronic rotator cuff tear model was created and RCR was performed. Postoperatively, osteoporotic rats were randomly divided into osteoporosis (OP) and osteoporosis with risedronate administration (OP+RIS) groups. Nonosteoporotic rats were used as the control (CON) group. Osteoclastic activity was measured at 1 and 3 weeks after RCR, and histologic analysis of the tendon-to-bone interface, bone morphometric evaluation, and biomechanical tests were performed at 4 and 8 weeks. RESULTS: At the early healing stages of 1 and 3 weeks after RCR, the OP group showed the highest osteoclast density at the repaired interface. Compared with the OP group, risedronate administration significantly decreased osteoclast density in the OP+RIS group. At 8 weeks, histologic scores were greater in the OP+RIS group than in the OP group but still lower than in the CON group. Histologic scores at 8 weeks were negatively correlated with osteoclast density at the early healing stage. Additionally, the OP+RIS group showed better bone morphometric parameters and biomechanical properties than did the OP group. CONCLUSION: Osteoporosis impaired rotator cuff healing, which might be related to the high osteoclast density at the repaired interface at the early healing stage. Postoperative risedronate administration decreased osteoclast density and enhanced rotator cuff healing in osteoporotic rats, although the effect was inferior to that in nonosteoporotic rats. CLINICAL RELEVANCE: Postoperative risedronate administration can be considered a potential therapy to enhance rotator cuff healing in patients with postmenopausal osteoporosis. However, this needs to be verified in a clinical setting.

Incomplete Rotator Cable Did Not Cause Rotator Cuff Dysfunction in Case of Rotator Cuff Tear: A Biomechanical Study of the Relationship Between Rotator Cable Integrity and Rotator Cuff Function.

PURPOSE: This study seeks to evaluate the biomechanical relationship between the severity of rotator cable tears and the function of the rotator cuff. METHODS: Twelve cadaveric shoulders with intact rotator cuff, existing rotator cable, and a critical shoulder angle below 35° were included. For each shoulder, a posterosuperior rotator cuff tear (PSRCT) (model 2) in the crescent area was formed. Then anterior insertion detached (model 3), anterior insertion detached together with the middle cable tear (model 4), and the whole rotator cable tear (model 5) were subsequently created. The rotator cuff that lay above the humeral head rotation center was detached as a global tear control (model 6), along with the primitive status as the intact control (model 1). Glenohumeral abduction was initiated by simulating deltoid and remaining rotator cuff force. Functioning of the remaining rotator cuff was evaluated using the middle deltoid force (MDF), as required for abduction. RESULTS: No statistically significant differences in peak MDF values were seen among the 4 PSRCT statuses (44.10 ± 7.30 N [model 2], P = .96; 45.50 ± 9.55 N [model 3], P = .86; 45.90 ± 3.53 N [model 4], P = 0.30; 44.20 ± 8.19 N [model 5], P = .80) and intact control status (39.79 ± 7.65 N [model 1]). However, significant differences in peak MDF values were found among the 4 PSRCT statuses and the global tear control status (54.53 ± 7.46 N [model 6], P < .01). CONCLUSION: The PSRCT, regardless of the severity of the rotator cable tear, does not induce functionally significant biomechanical impairment. Tear extension involving all rotator cuff tissue above the geometric rotation center of the humeral head results in obvious functional impairment. CLINICAL RELEVANCE: For PSRCT, the remaining rotator cuff tissue above the geometric rotation center may contribute to the preservation of shoulder function in RCT patients.