Injectable Hydrogel of Chitosan-Octyl Itaconate Conjugate Modulates Inflammatory Response.

Itaconic acid and its derivative 4-octyl itaconate (OI) represent a novel anti-inflammatory medication that has demonstrated efficacy in multiple inflammation models because of its minimal side effects. Recently, natural polymers conjugated with small molecule drugs, known as polymer-drug conjugates (PDCs), have emerged as a promising approach to sustained drug release. In this work, we reported an approach to prepare a PDC containing an OI and make it into an injectable hydrogel. Chitosan (CS) was selected for PDC synthesis because of its abundant free amino groups that can be conjugated with molecules containing carboxyl groups by carbodiimide chemistry. We used an ethanol/water cosolvent system to synthesize a CS-OI conjugate via EDC/NHS catalysis. The CS-OI conjugate had improved water solubility and unique anti-inflammatory activity and did not show compromised antibacterial activity compared with unmodified CS. Beta-glycerophosphate (ß-GP) cross-linked CS-OI hydrogel exhibited good injectability with sustainable OI release and effectively modulated inflammatory response in a rat model. Therefore, this study provides valuable insights into the design of PDC hydrogels with inflammatory modulatory properties.

Bioactive Patch for Rotator Cuff Repairing via Enhancing Tendon-to-Bone Healing: A Large Animal Study and Short-Term Outcome of a Clinical Trial.

Tissue engineering has demonstrated its efficacy in promoting tissue regeneration, and extensive research has explored its application in rotator cuff (RC) tears. However, there remains a paucity of research translating from bench to clinic. A key challenge in RC repair is the healing of tendon-bone interface (TBI), for which bioactive materials suitable for interface repair are still lacking. The umbilical cord (UC), which serves as a vital repository of bioactive components in nature, is emerging as an important source of tissue engineering materials. A minimally manipulated approach is used to fabricate UC scaffolds that retain a wealth of bioactive components and cytokines. The scaffold demonstrates the ability to modulate the TBI healing microenvironment by facilitating cell proliferation, migration, suppressing inflammation, and inducing chondrogenic differentiation. This foundation sets the stage for in vivo validation and clinical translation. Following implantation of UC scaffolds in the canine model, comprehensive assessments, including MRI and histological analysis confirm their efficacy in inducing TBI reconstruction. Encouraging short-term clinical results further suggest the ability of UC scaffolds to effectively enhance RC repair. This investigation explores the mechanisms underlying the promotion of TBI repair by UC scaffolds, providing key insights for clinical application and translational research.

Fluffy hybrid nanoadjuvants for reversing the imbalance of osteoclastic and osteogenic niches in osteoporosis.

Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite the development of nationally recognized first-line anti-osteoporosis drugs, including alendronate (AL), their low bioavailability, poor uptake rate, and dose-related side effects present significant challenges in treatment. This calls for an urgent need for more effective bone-affinity drug delivery systems. In this study, we produced hybrid structures with bioactive components and stable fluffy topological morphology by cross-linking calcium and phosphorus precursors based on mesoporous silica to fabricate nanoadjuvants for AL delivery. The subsequent grafting of -PEG-DAsp8 ensured superior biocompatibility and bone targeting capacity. RNA sequencing revealed that these fluffy nanoadjuvants effectively activated adhesion pathways through CARD11 and CD34 molecular mechanisms, hence promoting cellular uptake and intracellular delivery of AL. Experiments showed that small-dose AL nanoadjuvants effectively suppress osteoclast formation and potentially promote osteogenesis. In vivo results restored the balance between osteogenic and osteoclastic niches against osteoporosis as well as the consequent significant recovery of bone mass. Therefore, this study constructed a drug nanoadjuvant with peculiar topological structures and high bone targeting capacities, efficient intracellular drug delivery as well as bone bioactivity. This provides a novel perspective on drug delivery for osteoporosis and treatment strategies for other bone diseases.

Decellularization-Based Modification Strategy for Bioactive Xenografts Promoting Tendon Repair.

Xenografts have emerged as a promising option for severe tendon defects treatment. However, despite undergoing decellularization, concerns still remain regarding the immunogenicity of xenografts. Because certain components within the extracellular matrix also possess immunogenicity. In this study, a novel strategy of post-decellularization modification aimed at preserving the endogenous capacity of cells on collagen synthesis to mask antigenic epitopes in extracellular matrix is proposed. To implement this strategy, a human-derived rosiglitazone-loaded decellularized extracellular matrix (R-dECM) is developed. R-dECM can release rosiglitazone for over 7 days in vitro. By suppressing M1 macrophage polarization, R-dECM protects the migration and collagen synthesis abilities of tendon-derived stem cells (TDSCs), while also stabilizing the phenotype of M2 macrophages in vitro. RNA sequencing reveals R-dECM can mitigate the detrimental crosstalk between TDSCs and inflammatory cells. When applied to a rat patellar tendon defect model, R-dECM effectively inhibits early inflammation, preventing chronic inflammation. Its duration of function far exceeds the release time of rosiglitazone, implying the establishment of immune evasion, confirming the effectiveness of the proposed strategy. And R-dECM demonstrates superior tendon repair outcomes compared to dECM. Thus, this study provides a novel bioactive scaffold with the potential to enhance the long-term clinical outcomes of xenogeneic tendon grafts.

Bi-lineage inducible and immunoregulatory electrospun fibers scaffolds for synchronous regeneration of tendon-to-bone interface.

Facilitating regeneration of the tendon-to-bone interface can reduce the risk of postoperative retear after rotator cuff repair. Unfortunately, undesirable inflammatory responses following injury, difficulties in fibrocartilage regeneration, and bone loss in the surrounding area are major contributors to suboptimal tendon-bone healing. Thus, the development of biomaterials capable of regulating macrophage polarization to a favorable phenotype and promoting the synchronous regeneration of the tendon-to-bone interface is currently a top priority. Here, strontium-doped mesoporous bioglass nanoparticles (Sr-MBG) were synthesized through a modulated sol-gel method and Bi-lineage Inducible and Immunoregulatory Electrospun Fibers Scaffolds (BIIEFS) containing Sr-MBG were fabricated. The BIIEFS were biocompatible, showed sustained release of multiple types of bioactive ions, enhanced osteogenic and chondrogenic differentiation of mesenchymal stem cells (MSCs), and facilitated macrophage polarization towards the M2 phenotype in vitro. The implantation of BIIEFS at the torn rotator cuff resulted in greater numbers of M2 macrophages and the synchronous regeneration of tendon, fibrocartilage, and bone at the tendon-to-bone interface, leading to a significant improvement in the biomechanical strength of the supraspinatus tendon-humerus complexes. Our research offers a feasible strategy to fabricate immunoregulatory and multi-lineage inducible electrospun fibers scaffolds incorporating bioglass nanoparticles for the regeneration of soft-to-hard tissue interfaces.

Rotator cuff tear reaching the superior half portion of the humeral head causes shoulder abduction malfunction.

PURPOSE: To examine the biomechanical properties governing posterosuperior rotator cuff (RC) tear progression and dynamic shoulder abduction function, in the absence of excess loading. METHODS: Twelve freshly frozen cadaveric shoulders were evaluated via an established dynamic shoulder abduction stimulator. The shoulder abduction functions were primarily evaluated using subacromial contact pressure (SACP) during an abduction procedure, and subsequent middle deltoid force (MDF) under 5 conditions: (1) intact, (2) anterior 1/3 posterosuperior rotator cuff (PSRC) tear, (3) anterior 2/3 PSRC tear, (4) entire PSRC tear, and (5) global RC tear (tear involving the entire superior RC). RESULTS: No obvious differences were observed in the peak MDF required for abduction, and in the peak SACP among the four PSRC tear statuses (49.8 ± 9.2 N, 0.39 ± 0.05 mPa [1/3 PSRC tear]; 49.3 ± 6.8 N, 0.40 ± 0.06 mPa [2/3 PSRC tear]; 51.6 ± 7.0 N, 0.44 ± 0.08 mPa [entire PSRC tear]), as well as intact statuses (48.3 ± 9.8 N, 0.40 ± 0.05 mPa). However, significant elevations in the peak MDF and peak SACP levels were observed among the four PSRC tear statuses and global RC tear (68.1 ± 9.3 N; 4.12 ± 1.50 mPa, P < 0.01). CONCLUSION: In the absence of excess loading, the biomechanical function of the shoulder was not impaired by a simple PSRC tear. However, once the tear size reached the half superior portion of the humeral head, the humeral head migrated to the surface of the subacromion, and this action markedly decreased shoulder abduction function.

Regulating Macrophages through Immunomodulatory Biomaterials Is a Promising Strategy for Promoting Tendon-Bone Healing.

The tendon-to-bone interface is a special structure connecting the tendon and bone and is crucial for mechanical load transfer between dissimilar tissues. After an injury, fibrous scar tissues replace the native tendon-to-bone interface, creating a weak spot that needs to endure extra loading, significantly decreasing the mechanical properties of the motor system. Macrophages play a critical role in tendon-bone healing and can be divided into various phenotypes, according to their inducing stimuli and function. During the early stages of tendon-bone healing, M1 macrophages are predominant, while during the later stages, M2 macrophages replace the M1 macrophages. The two macrophage phenotypes play a significant, yet distinct, role in tendon-bone healing. Growing evidence shows that regulating the macrophage phenotypes is able to promote tendon-bone healing. This review aims to summarize the impact of different macrophages on tendon-bone healing and the current immunomodulatory biomaterials for regulating macrophages, which are used to promote tendon-bone healing. Although macrophages are a promising target for tendon-bone healing, the challenges and limitations of macrophages in tendon-bone healing research are discussed, along with directions for further research.

Relationship between the progression of posterosuperior rotator cuff tear size and shoulder abduction function: A cadaveric study via dynamic shoulder simulator.

Posterosuperior rotator cuff tear (PSRCT) is one of the most common shoulder disorders in elderly people's daily life; however, the biomechanical relationship between PSRCT and shoulder abduction function is still controversial. In this study, a total of twelve freshly frozen cadaveric shoulders were included and tested in five conditions: intact rotator cuff, 1/3 PSRCT, 2/3 PSRCT, entire PSRCT, and global RCT. In each condition, extra load (0%, 45%, and 90% failure load) was sequentially added to the distal humerus, and the function of the remaining rotator cuff was mainly evaluated via the middle deltoid force (MDF) required for abduction. It is found that the peak MDF is required for abduction did not differ among the three PSRCT conditions (1/3 PSRCT: 29.30 ± 5.03 N, p = 0.96; 2/3 PSRCT: 29.13 ± 9.09 N, p = 0.98; entire PSRCT: 28.85 ± 7.12 N, p = 0.90) and the intact condition (29.18 ± 4.99 N). However, the peak MDF significantly differed between the global RCT (76.27 ± 4.94 N, p < 0.01) and all PSRCT and intact conditions. Under 45% failure load, the MDF of the entire PSRCT and global tear conditions were significantly increased compared with another status. With the 90% failure load, only the 1/3 PSRCT condition maintained the same shoulder function as the intact rotator cuff. These biomechanical testing jointly suggested that the weight-bearing ability of the shoulder significantly decreased as PSRCT progressed.

Crimped nanofiber scaffold mimicking tendon-to-bone interface for fatty-infiltrated massive rotator cuff repair.

Electrospun fibers, with proven ability to promote tissue regeneration, are widely being explored for rotator cuff repairing. However, without post treatment, the microstructure of the electrospun scaffold is vastly different from that of natural extracellular matrix (ECM). Moreover, during mechanical loading, the nanofibers slip that hampers the proliferation and differentiation of migrating stem cells. Here, electrospun nanofiber scaffolds, with crimped nanofibers and welded joints to biomimic the intricate natural microstructure of tendon-to-bone insertion, were prepared using poly(ester-urethane)urea and gelatin via electrospinning and double crosslinking by a multi-bonding network densification strategy. The crimped nanofiber scaffold (CNS) features bionic tensile stress and induces chondrogenic differentiation, laying credible basis for in vivo experimentation. After repairing a rabbit massive rotator cuff tear using a CNS for 3 months, the continuous translational tendon-to-bone interface was fully regenerated, and fatty infiltration was simultaneously inhibited. Instead of micro-CT, µCT was employed to visualize the integrity and intricateness of the three-dimensional microstructure of the CNS-induced-healed tendon-to-bone interface at an ultra-high resolution of less than 1 µm. This study sheds light on the correlation between nanofiber post treatment and massive rotator cuff repair and provides a general strategy for crimped nanofiber preparation and tendon-to-bone interface imaging characterization.