Bioprinting-Enabled Biomaterials: A Cutting-Edge Strategy for Future Osteoarthritis Therapy.

Bioprinting is an advanced technology that allows for the precise placement of cells and biomaterials in a controlled manner, making significant contributions in regenerative medicine. Notably, bioprinting-enabled biomaterials have found extensive application as drug delivery systems (DDS) in the treatment of osteoarthritis (OA). Despite the widespread utilization of these biomaterials, there has been limited comprehensive research summarizing the recent advances in this area. Therefore, this review aims to explore the noteworthy developments and challenges associated with utilizing bioprinting-enabled biomaterials as effective DDS for the treatment of OA. To begin, we provide an overview of the complex pathophysiology of OA, highlighting the shortcomings of current treatment modalities. Following this, we conduct a detailed examination of various bioprinting technologies and discuss the wide range of biomaterials employed in DDS applications for OA therapy. Finally, by placing emphasis on their transformative potential, we discuss the incorporation of crucial cellular components such as chondrocytes and mesenchymal stem cells into bioprinted constructs, which play a pivotal role in promoting tissue regeneration and repair.

[Progress in clinical diagnosis and treatment of diabetic Charcot neuroarthropathy of foot and ankle].

Objective: To summarize the progress of clinical diagnosis and treatment of diabetic Charcot neuroarthropathy (CNO) of foot and ankle to provide reference for clinical treatment. Methods: The research literature on diabetic CNO of foot and ankle at home and abroad was widely reviewed, and the stages and classification criteria of CNO were summarized, and the treatment methods at different stages of the disease course were summarized. Results: CNO is a rapidly destructive disease of bone and joint caused by peripheral neuropathy, which leads to the formation of local deformities and stress ulcers due to bone and joint destruction and protective sensory loss, which eventually leads to disability and even life-threatening. At present, the modified Eichenholtz stage is a commonly used staging criteria for CNO of foot and ankle, which is divided into 4 stages by clinical and imaging manifestations. The classification mainly adopts the modified Brodsky classification, which is divided into 6 types according to the anatomical structure. The treatment of diabetic CNO of foot and ankle needs to be considered in combination with disease stage, blood glucose, comorbidities, local soft tissue conditions, degree of bone and joint destruction, and whether ulcers and infections are present. Conservative treatment is mainly used in the active phase and surgery in the stable phase. Conclusion: The formulation of individualized and stepped treatment regimens can help improve the effectiveness of diabetic CNO of foot and ankle. However, there is still a lack of definitive clinical evidence to guide the treatment of active and stable phases, and further research is needed.

[Effectiveness and risk factors of supramalleolar osteotomy in treatment of varus-type ankle arthritis].

Objective: To assess the effectiveness of supramalleolar osteotomy (SMOT) as a therapeutic intervention for varus-type ankle arthritis, while also examining the associated risk factors that may contribute to treatment failure. Methods: The clinical data of 82 patients (89 feet) diagnosed with varus-type ankle arthritis and treated with SMOT between January 2016 and December 2020 were retrospectively analyzed. The patient cohort consisted of 34 males with 38 feet and 48 females with 51 feet, with the mean age of 54.3 years (range, 43-72 years). The average body mass index was 24.43 kg/m 2 (range, 20.43-30.15 kg/m 2). The preoperative tibial anterior surface angle (TAS) ranged from 77.6° to 88.4°, with a mean of 84.4°. The modified Takakura stage was used to classify the severity of the condition, with 9 feet in stage Ⅱ, 41 feet in stage Ⅲa, and 39 feet in stage Ⅲb. Clinical functional assessment was conducted using the Maryland sore, visual analogue scale (VAS) score, and psychological and physical scores in Health Survey 12-item Short From (SF-12). Radiology evaluations include TAS, talar tilt (TT), tibiocrural angle (TC), tibial medial malleolars (TMM), tibiocrural distance (TCD), tibial lateral surface angle (TLS), and hindfoot alignment angle (HAA). The results of clinical failure, functional failure, and radiology failure were statistically analyzed, and the related risk factors were analyzed. Results: The operation time ranged from 45 to 88 minutes, with an average of 62.2 minutes. No complication such as fractures and neurovascular injuries was found during operation. There were 7 feet of poor healing of the medial incision; 9 pin tract infections occurred in 6 feet using external fixator; there were 20 cases of allograft and 3 cases of autograft with radiographic bone resorption. Except for 1 foot of severe infection treated with bone cement, the remaining 88 feet were primary healing, and the healing area was more than 80%. All patients were followed up 24-82 months, with an average of 50.2 months. Maryland score, VAS score, SF-12 psychological and physiological scores, and TAS, TC, TLS, TCD, TT, TMM, HAA, and Takakura stage were significantly improved at last follow-up ( P<0.05). Postoperative clinical failure occurred in 13 feet, functional failure in 15 feet, and radiology failure in 23 feet. Univariate analysis showed that obesity, TT>10°, and Takakura stage Ⅲb were risk factors for clinical failure, HAA≥15° and Takakura stage Ⅲb were risk factors for functional failure, and TT>10° was risk factor for radiographic failure ( P<0.05). Further logistic regression analysis showed that TT>10°, HAA≥15°, and TT>10° were risk factors for clinical failure, functional failure, and radiographic failure, respectively ( P<0.05). Conclusion: SMOT is effective in the mid- and long-term in the treatment of varus-type ankle arthritis, but it should be used with caution in patients with obesity, severe hindfoot varus, severe talus tilt, and preoperative Takakura stage Ⅲb.

Cartilage Damage Pathological Characteristics of Diabetic Neuropathic Osteoarthropathy.

Background: Diabetic neuropathic osteoarthropathy (DNOAP) is a rare and easily missed complication for diabetes that leads to increased morbidity and mortality. DNOAP is characterized by progressive destruction of bone and joint, but its pathogenesis remains elusive. We herein aimed to investigate the pathological features and pathogenesis of the cartilages damage in DNOAP patients. Methods: The articular cartilages of eight patients with DNOAP and eight normal controls were included. Masson staining and safranine O/fixed green staining (S-O) were used to observe the histopathological characteristics of cartilage. The ultrastructure and morphology of chondrocytes were detected by electron microscopy and toluidine blue staining. Chondrocytes were isolated from DNOAP group and control group. The expression of receptor activator of nuclear factor kappaB ligand (RANKL), osteoprotegerin (OPG), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and Aggrecan protein was evaluated by western blot. Reactive oxygen species (ROS) levels were measured using a 2',7'-dichlorofluorescin diacetate (DCFH-DA) probe. The percentage of apoptotic cells was determined by flow cytometry (FCM). The chondrocytes were cultured with different glucose concentrations to observe the expression of RANKL and OPG. Results: Compared with the control group, the DNOAP group showed fewer chondrocytes, subchondral bone hyperplasia, and structural disorder, and a large number of osteoclasts formed in the subchondral bone area. Moreover, mitochondrial and endoplasmic reticulum swellings were observed in the DNOAP chondrocytes. The chromatin was partially broken and concentrated at the edge of nuclear membrane. The ROS fluorescence intensity of chondrocyte in DNOAP group was higher than that in normal control group (28.1 ± 2.3 vs. 11.9 ± 0.7; P < 0.05). The expression of RANKL, TNF-α, IL-1ß, and IL-6 protein in DNOAP group was higher than that in normal control group, whereas OPG and Aggrecan protein were lower than that in normal control group (both P < 0.05). FCM showed that the apoptotic rate of chondrocyte in DNOAP group was higher than that in normal control group (P < 0.05). The RANKL/OPG ratio showed significant upward trend when the concentration of glucose was over than 15 mM. Conclusions: DNOAP patients tend to have severe destruction of articular cartilage and collapse of organelle structure including mitochondrion and endoplasm reticulum. Indicators of bone metabolism (RANKL and OPG) and inflammatory cytokines (IL-1ß, IL-6, and TNF-α) play an important role in promoting the pathogenesis of DNOAP. The glucose concentration higher than 15 mM made the RANKL/OPG ratio change rapidly.

[Calcaneal V-shaped osteotomy combined with subtalar arthrodesis for Stephens â ¡ and â ¢ calcaneal fractures malunion].

Objective: To investigate the effectiveness of calcaneal V-shaped osteotomy combined with subtalar arthrodesis in the treatment of Stephens Ⅱand Ⅲ calcaneal fracture malunion. Methods: The clinical data of 24 patients with severe calcaneal fracture malunion treated by calcaneal V-shaped osteotomy combined with subtalar arthrodesis between January 2017 and December 2021 were retrospectively analyzed. There were 20 males and 4 females with an average age of 42.8 years (range, 33-60 years). Conservative treatment of calcaneal fracture failed in 19 cases and operation failed in 5 cases. Stephens classification of calcaneal fracture malunion was type Ⅱ in 14 cases, and type Ⅲ in 10 cases. Preoperative Böhler angle of calcaneus was 4.0°-13.5° (mean, 8.6°), Gissane angle was 100°-152° (mean, 119.3°). The time from injury to operation was 6-14 months (mean, 9.7 months). American Orthopedic Foot and Ankle Society (AOFAS) ankle and hindfoot score and visual analogue scale (VAS) score were used to evaluate the effectiveness before operation and at last follow-up. Bone healing was observed and the healing time was recorded. The talocalcaneal height, talus inclination angle, Pitch angle, calcaneal width, and hindfoot alignment angle were measured. Results: Necrosis of the cuticle edge of the incision occurred in 3 cases, which were cured by dressing change and oral administration of antibiotic therapy. The other incisions healed by first intention. All the 24 patients were followed up 12-23 months, with an average of 17.1 months. The foot shape of the patients recovered well, the shoes were restored to the size before injury, and there was no anterior ankle impingement. Bone union was achieved in all patients, and the healing time ranged from 12 to 18 weeks, with an average of 14.1 weeks. At last follow-up, no adjacent joint degeneration occurred in all patients; 5 patients had mild foot pain during walking, which had no significant impact on daily life and work; no patient needed revision surgery. The AOFAS ankle and hindfoot score was significantly higher than that before operation ( P<0.001), the results were excellent in 16 cases, good in 4 cases, and poor in 4 cases, and the excellent and good rate was 83.3%. The VAS score, talocalcaneal height, talus inclination angle, Pitch angle, calcaneal width, and hindfoot alignment angle were significantly improved after operation ( P<0.001). Conclusion: Calcaneal V-shaped osteotomy combined with subtalar arthrodesis can effectively relieve hindfoot pain, correct talocalcaneal height, restore talus inclination angle, and reduce the risk of nonunion after subtalar arthrodesis.

The first human induced pluripotent stem cell line of Kashin-Beck disease reveals involvement of heparan sulfate proteoglycan biosynthesis and PPAR pathway.

Kashin-Beck disease (KBD) is an endemic osteochondropathy. Due to a lack of suitable animal or cellular disease models, the research progress on KBD has been limited. Our goal was to establish the first disease-specific human induced pluripotent stem cell (hiPSC) cellular disease model of KBD, and to explore its etiology and pathogenesis exploiting transcriptome sequencing. HiPSCs were reprogrammed from dermal fibroblasts of two KBD and one healthy control donor via integration-free vectors. Subsequently, hiPSCs were differentiated into chondrocytes through three-week culture. Gene expression profiles in KBD, normal primary chondrocytes, and hiPSC-derived chondrocytes were defined by RNA sequencing. A Venn diagram was constructed to show the number of shared differentially expressed genes (DEGs) between KBD and normal. Gene oncology and Kyoto Encyclopedia of Genes and Genomes annotations were performed, and six DEGs were further validated in other individuals by RT-qPCR. KBD cellular disease models were successfully established by generation of hiPSC lines. Seventeen consistent and significant DEGs present in all compared groups (KBD and normal) were identified. RT-qPCR validation gave consistent results with the sequencing data. Glycosaminoglycan biosynthesis-heparan sulfate/heparin; PPAR signaling pathway; and cell adhesion molecules (CAMs) were identified to be significantly altered in KBD. Differentiated chondrocytes derived from KBD-origin hiPSCs provide the first cellular disease model for etiological studies of KBD. This study also provides new sights into the pathogenesis and etiology of KBD and is likely to inform the development of targeted therapeutics for its treatment.

The RANK/RANKL/OPG system and tumor bone metastasis: Potential mechanisms and therapeutic strategies.

With the markedly increased diagnosis and incidence of cancer in the population, tumor bone metastasis has become a frequent event in tumor patients. Healthy bone integrity is maintained by a delicate balance between bone formation and bone resorption. Unfortunately, many tumors, such as prostate and breast, often metastasize to the bone, and the alterations to the bone homeostasis can particularly favor tumor homing and consequent osteolytic or osteoblastic lesions. Receptor activator of NF-κB ligand (RANKL), its receptor RANK, and osteoprotegerin (OPG) are involved in the regulation of the activation, differentiation, and survival of osteoclasts, which play critical roles in bone metastasis formation. High rates of osteoclastic bone resorption significantly increase fracture risk, cause severe bone pain, and contribute to homing tumor cells in bone and bone marrow. Consequently, suppression of the RANK/RANKL/OPG system and osteoclastic activity can not only ameliorate bone resorption but may also prevent tumor bone metastases. This review summarizes the important role of the RANK/RANKL/OPG system and osteoclasts in bone homeostasis and its effect on tumor bone metastasis and discusses therapeutic strategies based on RANKL inhibition.

Fibular osteotomy is helpful for talar reduction in the treatment of varus ankle osteoarthritis with supramalleolar osteotomy.

BACKGROUND: There have been debates on the necessity of fibular osteotomy (FO) in supramalleolar osteotomy (SMOT) for the treatment of varus ankle osteoarthritis. The purpose of the current study was to compare the clinical and radiological outcomes between SMOT with and without FO in the treatment of varus ankle osteoarthritis. METHODS: The SMOT group included 39 patients, and the SMOT with FO group included 24 patients. The basic information reached no significant difference between groups. The American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, Ankle Osteoarthritis Scale (AOS), modified Takakura stage and range of motion (ROM) were used for the functional evaluation. The radiologic parameters were assessed at the last follow-up to compare the degree of talar reduction between the two groups. RESULTS: Both groups achieved significant improvements in AOFAS scores, modified Takakura stage, as well as AOS pain and functional scores (P < 0.001). The ROM of the ankle joint in the SMOT group was significantly decreased (P = 0.022). In both groups, all of the radiological parameters were significantly improved (P < 0.01). The tibiofibular clear space (TFCS) was significantly widened in the SMOT group (P < 0.001). No significant difference was found between the two groups according to the functional outcomes. However, the talar tilt angle (TT) and hindfoot alignment angle (HFA) in the SMOT with FO group were significantly smaller than those in the SMOT group (P < 0.05). The TFCS was significantly widened in the SMOT group (P = 0.001). The medial displacement of the talus (MDT) was better reduced in the SMOT with FO group (P = 0.006). CONCLUSION: SMOT is a promising procedure for functional improvement and malalignment correction in varus ankle osteoarthritis but reduces ankle range of motion. If SMOT is combined with FO, talar tilt and medial displacement will be better reduced.

Ilizarov Gradual Distraction Correction for Distal Tibial Severe Varus Deformity Resulting from Epiphyseal Fracture: Case Report and Literature Review.

We present a case of a 13-year-old female with severe varus deformity and limb discrepancy resulting from epiphyseal fracture. The preoperative tibial articular surface angle was 64.1°, and the affected tibia was 14 mm shorter than the contralateral tibia. She underwent a medial open osteotomy and fibular osteotomy with gradual distraction correction using Ilizarov fixator. The deformity was corrected at 3 months, and the external fixator was removed when bony union was achieved 6 months postoperatively. At 9 months after surgery, the patient could play basketball without feeling pain. At the last follow-up, namely 36 months after the operation, the American Orthopaedic Foot and Ankle Society hindfoot-ankle score was improved from 58 to 90, the patient was pain free, and the radiological measurements were nearly normal. Ilizarov fixator gradual distraction correction for distal tibial severe varus deformity is a safe and cost-effective method that can yield excellent radiological and clinical outcomes.

[Research progress in Achilles tendinopathy].

OBJECTIVE: To explore the classification, diagnosis, and clinical treatment of Achilles tendinopathy. METHODS: The literature about Achilles tendinopathy at home and abroad was reviewed. The research results of classification and terms, imaging diagnosis, and clinical treatment of Achilles tendinopathy were summarized. RESULTS: The classification and name of Achilles tendinopathy are not completely unified, and the concept is vague, the cause of disease is not clear. There are many treatment plans, but there is no effective evidence-based medicine research. CONCLUSION: The diagnosis and treatment of Achilles tendinopathy is complicated. According to the characteristics of Achilles tendon anatomy and etiology, the classification and definition of Achilles tendinopathy need to be further studied in order to guide clinical treatment more effectively and facilitate experience exchange and learning.

Supramalleolar osteotomy with medial distraction arthroplasty for ankle osteoarthritis with talar tilt.

BACKGROUND: An increased preoperative talar tilt (TT) angle was reported to be positively correlated with treatment failure after supramalleolar osteotomy (SMOT) for varus ankle osteoarthritis. Distraction arthroplasty was reported to have the ability to correct increased TT angles. The purpose of the current study was to compare the outcomes between SMOT with and without medial distraction arthroplasty (MDA) in the treatment of varus ankle osteoarthritis with increased TT angles. METHODS: We retrospectively reviewed the functional outcomes and radiological findings of 34 patients who underwent SMOT with or without MDA for varus ankle osteoarthritis with increased TT angles. The American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score and Ankle Osteoarthritis Scale (AOS) scores were used for functional evaluation. The tibial anterior surface (TAS) angle, talar tilt (TT) angle, tibial medial malleolar (TMM) angle, talocrural (TC) angle, tibial lateral surface (TLS) angle, and hindfoot alignment (HFA) angle were evaluated preoperatively and at the time of the last follow-up. RESULTS: In the SMOT group, the AOFAS score and AOS pain and function scores were significantly improved (P < 0.01 for each) at a mean follow-up of 61 months. The TAS, TT, TC, TLS, and HFA angles were all significantly improved (P < 0.01 for each). Similarly, in the SMOT with MDA group, the AOFAS score, AOS pain and function scores, and the TAS, TT, TC, TLS, and HFA angles were all significantly improved postoperatively (P < 0.01 for each). When comparing the two groups, the postoperative TT angle was significantly smaller in the SMOT with MDA group (P = 0.023) than in the SMOT group. In addition, the failure rate of TT angle correction was significantly higher in the SMOT group (P = 0.016) than in the SMOT with MDA group. CONCLUSION: SMOT is a promising procedure for functional improvement and malalignment correction for varus ankle osteoarthritis, even in patients with increased talar tilt. If SMOT is combined with MDA, there can be an improvement in the correction of the increased talar tilt. LEVEL OF EVIDENCE: Level III, a retrospective comparative study.

[Effectiveness comparison between Scarf osteotomy combined with Akin osteotomy fixed by absorbable screws and fixed by metal screws for the treatment of moderate to severe hallux valgus].

Objective: To evaluate the effectiveness of Scarf osteotomy combined with Akin osteotomy in the treatment of moderate to severe hallux valgus with absorbable screws or metal screws fixation by clinical and radiological data. Methods: Between March 2014 and May 2016, the Scarf osteotomy combined with Akin osteotomy was used to treat 62 patients (83 feet) with moderate to severe hallux valgus. Twenty-five patients (35 feet) were fixed by absorbable screws (group A) and 37 patients (48 feet) were fixed by metal screws (group B). The difference in gender, age, affected side, etiology, severity, disease duration, preoperative hallux valgus angle (HVA) and first-second intermetatarsal angle (1-2IMA) measured in weight-bearing anteroposterior X-ray film, preoperative American Orthopaedic Foot and Ankle Society (AOFAS) scores and visual analogue scale (VAS) scores between 2 groups ( P>0.05). The complications and healing time of 2 groups were recorded and compared. At last follow-up, the AOFAS and VAS scores, and HVA, 1-2IMA measured by weight-bearing anteroposterior X-ray film were used to evaluate the effectiveness. Results: All incisions healed by first intention and no incision-related complication occurred in the two groups after operation. Both groups were followed up, the follow-up time in group A was 12-36 months (mean, 24.4 months) and in group B was 14-38 months (mean, 25.7 months). In group A, 1 foot was complicated with hallux varus, 2 feet had mild stiffness, 1 foot appeared metastatic metatarsal pain, and in group B was 2, 3, 2 feet, respectively. There was no recurrence of hallux valgus in both groups. The difference in the incidence of complications between the two groups after the first operation was not significant ( χ2=0.275, P=0.843). The removal rate of internal fixator in group B was 89.2% (33 cases) during the second operation, among which 3 cases had screw slip and 1 case had screw fracture. And 10.8% (4 cases) refused the second removal operation due to their age. Postoperative X-ray films showed that both groups had good healing at the osteotomy site, and there was no significant difference in healing time between the two groups ( t=1.633, P=0.285). At last follow-up, the AOFAS score, VAS score, HVA, and 1-2IMA were significantly improved in the two groups when compared with preoperative ones ( P<0.05); but no significant difference was found between the two groups ( P>0.05). Conclusion: The effectiveness of Scarf osteotomy combined with Akin osteotomy in the treatment of moderate to severe hallux valgus is significant, with few complications. Compared with being fixed by metal screws, being fixed by absorbable screws has the same effectiveness, but can avoid the risk of second operation to remove the internal fixator.

Dysregulation of MALAT1 and miR-619-5p as a prognostic indicator in advanced colorectal carcinoma.

The present study aimed to detect the expression of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and microRNA (miR)-619-5p in colorectal carcinoma (CRC), and to evaluate the significance of MALAT1 and miR-619-5p expression in the clinical diagnosis and prognosis of CRC. Quantitative polymerase chain reaction was used to detect MALAT1 and miR-619-5p expression in 120 colorectal carcinoma and 120 adjacent normal tissue samples. The expression levels of MALAT1 and miR-619-5p were significantly different between colorectal carcinoma and adjacent normal tissues (P<0.05). MALAT1 exhibited an average 2.52-fold increase in colorectal adenoma when compared with adjacent normal tissues, while miR-619-5p exhibited an average 5.79-fold decrease in colorectal adenoma when compared with adjacent normal tissues. There was a significant difference between the MALAT1 expression in CRC tissues obtained from men and women (P=0.027), and in tumor-node-metastasis (TNM) stage II and stage III lesions (P=0.019). MALAT1 expression was associated with lymphovascular invasion (P=0.047) and perineural invasion (P=0.012). In addition, miR-619-5p expression was also significantly different between men and women (P=0.032), and between TNM stage II and stage III lesions (P=0.012). miR-619-5p expression was also associated with lymphovascular invasion (P=0.023) and perineural invasion (P=0.009). Patients with high expression of MALAT1 and low expression of miR-619-5p demonstrated significantly shorter disease-free survival (DFS) (P=0.002) and overall survival (OS) times (P=0.004) compared with patients with low MALAT1 expression and high miR-619-5p expression. Patients with perineural invasion demonstrated significantly shorter DFS (P=0.001) and OS times (P=0.003) compared with patients without perineural invasion. In addition, there was a negative correlation between MALAT1 expression and miR-619-5p expression (r=-0.415, P=0.004) in CRC tissues. In conclusion, MALAT1 and miR-619-5p have potential for the molecular diagnosis of CRC patients, and combined assaying of MALAT1 and miR-619-5p may improve the accuracy of the diagnosis of CRC and act as a good prognostic indicator in CRC patients.