Joint Repair Research Articles

Mesenchymal Stem Cells for Treatment of Coxofemoral Dysplasia in a Dog

Background: Coxofemoral dysplasia (CFD) is the abnormal development of the hip joint, mostly affecting large breeds, and is characterized by subluxation or complete luxation of the femoral head. Among the conservative therapeutic options, cell therapies with stem cells for CFD provides potential by the countless possibilities of therapeutic application, especially those related to the chronic and/or degenerative diseases treatment, which could be a key point for the bone and joint repair. The objective was to report a bilateral CFD case in a dog, treated with intra-articular application of mesenchymal stem cells (MSC), with 0, 30, 60 and 90 days, and further evaluations. Case: A 2-year-old male Akita dog was referred to the Veterinary Hospital Harmonia (HVH) located in the city of Recife, Pernambuco, presenting clinical signs of hip pain, lameness and pelvic limbs hopping. By orthopedic examination, pain was observed at the cranial and caudal extension of the pelvic limb, and at flexion, abduction and adduction of the limb, as well as moderate muscle atrophy and presence of joint crackling. By coxofemoral radiography performed in ventrodorsal projection, it were detected bilateral femoral head subluxation, thickening of the femoral neck and the presence of intra-articular osteophytes. These findings are compatible with the degeneration caused by the presence of CFD. Laboratory tests performed such as hemogram and biochemical had no changes. Thus, the patient had intra-articular application of allogeneic MSC, derived from adipose tissue, obtained by private company. For stem cell applications, arthrocentesis of the hip joints was performed one at a time, using a 5 mL syringe and 16G needle for aspiration of 2 mL synovial fluid, for discard and application of stem cells. After aspiration, the syringe containing the MSC were fitted to the 16G needle for the implant. After the final procedure, the patient was moved to the internment division for anesthetic recovery. The animal was clinically assessed on days 0, 30, 60 and 90 following the criteria of locomotion and physical-orthopedic examination, in which the results were interpreted by a numerical scale. Discussion: For locomotion, there were differences for the pattern observed on days 0, 30, 60 and 90, with reduced claudication until walking without changes. There was also a decrease in the range of motion until limitations absent. For the parameters such as functional capacity and claudication at trot, there were reductions from the 30th day, promoting a slightly rigid gait, being noticeable when running. For the clinical parameters used in the physical-orthopedic evaluation, regarding the parameters analysis such as pain, caudal extension, cranial extension, internal rotation, abduction, and adduction, there were differences from the 30th day through pain reduction, remaining on the 60th and 90th days. Regarding the muscle atrophy, a difference was observed in the right pelvic limb on the 60th day, with moderate recovery. In addition, for the station tests and presence of joint crackling in the pelvic joint, there were no differences for the pattern during data collection regarding all evaluations. Those results allow inferring that MSC contributed to the CFD treatment, promoting the reduction of clinical signs and, consequently, providing a better life quality of the patient, which positively characterize it as a modality of treatment. Keywords: veterinary orthopedic, lameness, joint, genetic disease, degenerative disease. Título: Células-tronco mesenquimais para tratamento de displasia coxofemoral em cão Descritores: ortopedia veterinária, claudicação, articulação, doença genética, doença degenerativa.

Acromioclavicular joint suture button repair leads to coracoclavicular tunnel widening

PurposeBiomechanical evaluation of three different suture button devices used in acromioclavicular joint repair and analysis of their effect on post-testing tunnel widening.MethodsEighteen human shoulder girdles were assigned into three groups with a similar mean bone mineral density. Three different single-tunnel acromioclavicular repair devices were tested: (1) AC TightRope® with FiberWire; (2) AC Dog Bone™ Button with FiberTape; (3) Low Profile AC Repair System. Biomechanical testing was performed simulating the complex movement of the distal clavicle as follows. A vertical load of 80 N was applied continuously. The rotation of the clavicle about its long axis was set at 10° anterior and 30° posterior for 2500 cycles at 0.25 Hz. The horizontal translation of the clavicle was set at 6 mm medial and 6 mm lateral for 10,000 cycles at 1 Hz. The coracoclavicular distance was measured before and after testing. After testing, each sample underwent micro-CT analysis. Following 3D reconstruction, the area of the bone tunnels was measured at five defined cross sections.ResultsIn TightRope® and Dog Bone™ groups, all samples completed testing, whereas in the Low Profile group, three out of six samples showed system failure. The mean absolute difference of coracoclavicular distance after testing was significantly greater in the Low Profile group compared to TightRope® and Dog Bone™ groups (4.3 ± 1.3 mm vs 1.9 ± 0.7 mm vs 1.9 ± 0.8 mm; p = 0.001). Micro-CT analysis of the specimens demonstrated significant tunnel widening in the inferior clavicular and superior coracoid regions in all three groups (p < 0.05).ConclusionSignificant tunnel widening can be observed for all devices and is primarily found in the inferior parts of the clavicle and superior parts of the coracoid. The Low Profile AC Repair System showed inferior biomechanical properties compared to the AC TightRope® and AC Dog Bone™ devices. Therefore, clinicians should carefully select the type of acromioclavicular repair device used and need to consider tunnel widening as a complication.

Experimental research on mechanical properties of Fiber-Reinforced Polyurethane Elastic Concrete (FRPEC)

Given the shortcomings of conventional repair materials for bridge expansion joints, such as ease of damage and lengthy maintenance cycles, this research developed a new type of Fiber-Reinforced Polyurethane Elastic Concrete (FRPEC) that can be used for rapid repair of bridge expansion joints. FRPEC has the advantages of short setting time, high initial strength, excellent bonding performance and satisfactory deformation and toughness. The objective of this research was to explore and experimentally investigate the basic mechanical properties of the new material (FRPEC) such as failure mechanism, compressive strength and flexural strength, workability and toughness. The orthogonal test range analysis and analysis of variance (ANOVA) were used to optimize FRPEC mixtures based on the compressive and flexural strengths under varying P:CS ratio, cement proportion, and fiber content. Results show that a decrease in the P:CS ratio from 1:1.5 to 1:3 led to an improvement in the mechanical properties of FRPEC, whereas an increase in cement proportion from 40% to 70% adversely affected the mechanical properties. The incorporation of steel fiber improved the strength and toughness of FRPEC.

Autologous Oxygen-Releasing Nano-Biomimetic Scaffold with Chondrocytes Promotes Joint Repair After Trauma

Our study assesses the role of a scaffold constructed by co-culture of autologous oxygen-releasing biomimetic scaffold (AONS) and chondrocytes in joint repair after trauma. A composite scaffold structure was used and a scaffold constructed of AONS and chondrocytes was transplanted into SD rats to create models of patellar cartilage fracture and hip osteochondral fracture, respectively followed by analysis of cell proliferation by immunofluorescence method, osteogenesis-related gene expression by RT-PCR, chondrocytes apoptosis by TUNEL staining. The blank control group and AONS composite chondrocytes have significant differences in apoptosis and cell proliferation of two fracture types (P &lt;0.05). The autologous oxygen-releasing nanometers at 4 and 8 weeks showed a significant difference in the number of PCNA and TUNEL cells between biomimetic scaffold and chondrocytes in two groups (P &lt; 0.05). The AONS and chondrocytes were effective for two types of fractures at 1, 4 and 8 weeks. The expression of various markers of intrachondral osteogenesis was decreased and the markers of hip osteochondral fracture were increased significantly (P &lt; 0.05). Joint recovery was better than patellar cartilage fractures. The AONS composite chondrocyte scaffold promotes repair of patellar cartilage fractures and hip osteochondral fractures with a better effect on hip osteochondral fractures.

Arthroscopic Anatomical Acromioclavicular Joint Reconstruction using a Button Device and a Semitendinosus Graft.

ObjectiveTo report a new technique for anatomical acromioclavicular (AC) joint reconstruction.MethodsIn order to minimize such complications, the authors describe a new anatomical and biological AC joint repair. This technique aims to provide greater stability by using two anatomically placed clavicular tunnels and a combined construct with a double endobutton cortical fixation for primary stabilization, and to be biologically advantageous by using an autologous semitendinosus (ST) tendon graft. Additionally, the coracoclavicular ligament reconstruction is complemented with an AC joint cerclage and capsular reinforcement, which will protect the biological construction in its initial stage of healing.ResultsThis technique provides adequate primary and secondary biomechanical stability by passing both a semitendinosus autogenous graft and a double endobutton device, through anatomically placed and small diameter clavicle holes, without the need for coracoid drilling. Our technique showed encouraging results regarding pain resolution, range of motion, and function. At final follow‐up we experienced excellent results with average pain score of 1.6, and average ROM of 159° of forward flexion, 160° of abduction, 68° of external rotation, and internal rotation level at T11. Postoperative function also showed great improvements with average ASES of 85 points, an average Constant Score of 87 and a Subjective Shoulder Value of 89 points. This technique also achieved perfectly acceptable radiographic results, with an average coracoclavicular distance increase of 0.8 mm. Regarding complications, our sample showed one case of AC join subluxation, two cases of internal saphenous nerve injury, and two partial graft tears at the suture‐button interface, with none of these requiring surgical revision.ConclusionThis technique is advantageous in treatment of acromioclavicular joint dislocation and can be performed in both the subacute and chronic setting.

Red Cell Distribution Width: A Clinical Indicator to Assess Severity and Guide Anti-Inflammatory Therapy in Patients with Knee Osteoarthritis

To explore the influence factors of the red cell distribution width (RDW) level in knee osteoarthritis (KOA) patients, the difference in RDW before and after total knee arthroplasty (TKA), and further explain the clinical value of the RDW level in KOA patients. Information of 195 patients with KOA and 43 patients with meniscus injuries undergoing surgical treatment in the Surgery Department of Joint and Microsurgery Repair and the Surgery Department of Sports Trauma and Joint Arthroscopy of the First Affiliated Hospital of Anhui Medical University from June 1, 2020, to December 1, 2020, were collected. All included patients’ gender, age, height, medical history, blood lipid, erythrocyte sedimentation rate (ESR), CRP, RDW, anteroposterior and lateral X-ray images of the knee joint, and magnetic resonance imaging (MRI) of the knee joint were recorded. The difference in RDW of KOA patients with different severities before and after unilateral TKA surgery was compared, and the difference between KOA patients and patients with only meniscus injury was also compared for further analysis of the influence factors of the RDW level in moderate-severe KOA patients. Among moderate-severe KOA patients with different imaging severities, the RDW level was significantly different (P = 0.022). There was no statistical difference between the groups with and without the TKA history. The RDW level was higher in KOA patients than in patients with only meniscus injuries, and the difference was statistically significant P &lt; 0.05 . To some extent, the RDW level could be taken as a predictor for the severity of moderate-severe KOA patients, and its elevation was primarily related to chondritis and synovitis caused by KOA, so it was suggested that the patients receive adjuvant anti-inflammation therapy after TKA surgery.

Identification of Common Pathogenic Pathways Involved in Hemochromatosis Arthritis and Calcium Pyrophosphate Deposition Disease: a Review.

Arthritis is a common clinical manifestation of hereditary hemochromatosis (HH), and HH is one of a handful of conditions linked to calcium pyrophosphate deposition (CPPD) in joints. The connection between these two types of arthritis has not yet been fully elucidated. In light of new pathogenic pathways recently implicated in CPPD involving bone, we reviewed the literature on the etiology of hemochromatosis arthropathy (HHA) seeking shared pathogenic mechanisms. Clinical observations reinforce striking similarities between HHA and CPPD even in the absence of CPP crystals. They share a similar joint distribution, low grade synovial inflammation, and generalized bone loss. Excess iron damages chondrocytes and bone cells in vitro. While direct effects of iron on cartilage are not consistently seen in animal models of HH, there is decreased osteoblast alkaline phosphatase activity, and increased osteoclastogenesis. These abnormalities are also seen in CPPD. Joint repair processes may also be impaired in both CPPD and HHA. Possible shared pathogenic pathways relate more to bone and abnormal damage/repair mechanisms than direct damage to articular cartilage. While additional work is necessary to fully understand the pathogenesis of arthritis in HH and to firmly establish causal links with CPPD, this review provides some plausible hypotheses explaining the overlap of these two forms of arthritis.

Preparation and Biocompatibility Evaluation of Nanoscale Isoniazide-Loaded Mineralized Collagen Implants for Tuberculous Bone and Joint Repair.

Bone and joint tuberculosis is an extremely severe infectious disease that commonly occurs due to the primary infection of a type of mycobacteria, called Mycobacterium tuberculosis. Under the current scenario, there are very limited supplies of bone grafts available for the treatment of deceased bone, including autogenous bone and synthetic biomaterials. The present study aimed to construct a nanoscale isoniazid-loaded mineralized collagen implant, and then to explore its physicochemical properties and to investigate its biocompatibility suitable for bone and joint repair. Using type I collagen as raw material and the principle of biomimetic mineralization for self-assembly of bone tissue, a new drug-loaded mineralized collagen implant was constructed by molecular coprecipitation with isoniazid. Its surface morphology, elemental composition, and porosity were characterized by field emission scanning electron microscope (SEM), X-ray diffraction (XRD), and pycnometer. The performance of the implant was gauged by sustained release and degradation, which were studied using an ultraviolet spectrophotometer and a simulated in vivo environment. The drug loading and encapsulation rates of the implants were (6.25 ± 0.48)% and (54 ± 2.34)%, respectively. The in vitro release time of the scaffold was more than 12 weeks and the degradation performance was excellent. The scaffold was then implanted into mice, and the inflammatory reaction of local tissue was observed by Haemotoxylin and Eosin (H&E) and Masson. The in vivo evaluation in mice showed that the scaffold was biocompatible. Overall, compared with traditional drug loading systems, the isoniazid biomimetic mineralized collagen implant constructed here has better drug release performance, biodegradability, and biocompatibility. This kind of collagen implant may find potential applications in tuberculous bone and joint repair.

Simulation of crack growth in residual stress fields of pre-fatigued T-welded joints repaired by tungsten inert gas: a 3D approach

In this article, a three-dimensional finite element model (FEM) is used to predict the crack growth at the weld toe of a pre-fatigued T-joint that was repaired with a remelting technique. The numerical models were developed using the MSC.Marc software. Fatigue life is estimated by integrating the Paris-Erdogan law. The stress intensity factors are obtained by the virtual crack closure technique (VCCT).The T-welded joints, made of S355 steel, are obtained by covered electrode process and pre-cracked by fatigue. These welded joints were repaired by TIG dressing. The stress field generated by this dressing technique was estimated using a FEM model, presented in authors’ previous works. For the crack growth was used the VCCT three-dimensional model recently presented by the authors to predict the effect of overloads. The pre-existence of an elliptical crack at the weld toe, with a depth of 0.5 mm was considered. It is also studied the growth of pre-existing cracks which have been poorly repaired.It was observed that the TIG dressing produce residual compression stress fields on the weld toe that causes a delay in crack growth. The obtained results are compared with experimental ones. The fatigue’s lives obtained by simulations with the numerical model presented in this paper allows to evaluate the application conditions of TIG remelting technique in the repair of pre-cracked welded joints.

Retracted] Application of Nanoscaffold Material Combined with Exercise Rehabilitation Therapy in the Treatment of Athletes with Hip Injuries

A nanoscaffold is a porous scaffold. It injects antibiotics, cells, and polymer particles into damaged cavities in the form of injectables and forms hydrogels after the molecules self‐assemble at the injection site. Sports rehabilitation is a new frontier field integrating sports, health, and medicine, also known as physical therapy. It is the use of various sports methods for the injured or disabled, so that they can fully recover their physical functions and spirits, and can make them reintegrate into society. It mainly studies the relationship between sports and health. Among the tissue engineering scaffolds used as seed cell carriers, nanomaterials are playing an increasingly important role in the study of joint injury and repair due to their unique effects such as cell adhesion and proliferation. The purpose of this paper is to study a reliable nanoscaffold material for the treatment of patients with hip injuries in athletes and to observe its actual effect in combination with sports rehabilitation therapy. In this paper, an electrospinning method was proposed to prepare nanoscaffold materials, and the nanoscaffold materials were applied to the exercise rehabilitation process of two groups of hip patients, and the data of the patients’ rehabilitation were calculated. The results showed that the OD value of the cells in the exercise rehabilitation therapy using nanofiber scaffolds increased significantly, and the average daily growth rate of the OD value was 0.112. And the rehabilitation after 5 months was 19.8 points higher in hip range of motion score, 11.3 points higher in overall function score, and 6.2% lower in complication rate compared with ordinary exercise rehabilitation therapy. Therefore, it can be concluded that the therapy of the nanofiber scaffold material combined with exercise rehabilitation can more efficiently help patients with hip joint injury to recover, and the probability of complications is lower compared with the traditional exercise rehabilitation therapy.

JOINT REPAIR EVALUATED AUTOMATICALLY ON RADIOGRAPHS IS ASSOCIATED WITH PAIN AND SYNOVIAL FLUID MARKER CHANGES AFTER KNEE JOINT DISTRACTION TREATMENT

Knee joint distraction (KJD) has been associated with clinical and structural improvement and synovial fluid (SF) marker changes. However, structural changes have not yet been shown satisfactorily in regular care, since radiographic acquisition was not fully standardized. AI-based modules have shown great potential to reduce reading time, increase inter-reader agreement and therefore function as a tool for treatment outcome assessment. To 1) analyze structural changes after KJD in patients using this AI-based measurement method, and relate these changes to 2) clinical outcome and 3) SF markers. 20 knee OA patients (<65 years old) were included in this study. KJD treatment was performed using an external fixation device, providing 5 mm distraction for 6-7 weeks. SF was aspirated before, during and immediately after treatment. Weight-bearing antero-posterior knee radiographs and WOMAC questionnaires were collected before and ∼one year after treatment. Radiographs were analyzed with the Knee Osteoarthritis Labelling Assistant (KOALA, IB Lab GmbH, Vienna, Austria) to obtain whole-joint KL grade, medial and lateral joint space narrowing (JSN) scores, compartmental continuous minimum and standardized JSW, and osteophytes and sclerosis scores of the medial and lateral tibia and femur. 10 Pre-defined biomarker levels in SF were measured by immunoassay. Radiographic one-year changes were analyzed using Wilcoxon Signed Rank tests for categorical and paired t-test for continuous variables. Linear regression was used to calculate associations between changes in standardized joint space width (JSW) and WOMAC, and changes in JSW and SF markers. After treatment, radiographs showed an improvement in Kellgren-Lawrence grade in 7 of 16 patients that could be evaluated; 3 showed a worsening. Joint space narrowing scores and continuous JSW measures improved especially medially. Radiographic changes were not statistically significant (p>0.1), except for the medial JSW (p<0.05). A greater improvement in JSW was significantly associated with a greater improvement in WOMAC pain (β=0.64; p=0.020). A greater increase in MCP1 (β=0.67; p=0.033) and lower increase in TGFβ1 (β=-0.787; p=0.007) were associated with JSW improvement. Despite the small number of patients, also in regular care KJD treatment shows joint repair as measured automatically on radiographs, significantly associated with certain SF marker change and even with clinical outcome. Versus Arthritis project grant (20783), Centre for OA Pathogenesis Versus Arthritis (grants 20205 and 21621), the Kennedy Trust for Rheumatology Research, and ReumaNederland (ISP14-3-301/16-1-404). CS, EB, MD: ImageBiopsyLab GmbH. NA CORRESPONDENCE ADDRESS: m.p.jansen-36@umcutrecht.nl

Infrastructural Breaks on the Road from Birth to Death in Contemporary Russia

This paper addresses the problem of infrastructural breaks in two systems—the funeral market and maternity care. The authors analytically problematize how dysfunctions in the operation of these infrastructures shape the experiences of funeral and childbirth in contemporary Russia. The authors propose the conceptual model of the ‘rite of passage’, supplemented with the sociology of repair joint with the anthropology of infrastructures. Based on the ethnographic studies of the funeral market and maternity care (2015–2019), the authors uncover multiple infrastructural gaps and challenges that Russian families face while preparing for childbirth and funeral, especially in remote areas of the country. Empirical data of participant observations, in-depth and expert interviews demonstrated that continuous infrastructural failures can be considered to be an integral part of these life-cycle rituals, as both burial and maternity care arrangements never happen smoothly and unproblematically. In conclusion, the authors argue that necessity of “repairing” or patching the infrastructural gaps obtains self-sufficient symbolic meanings that possess ontological features.

Combination of Surgical Techniques Restores Multidirectional Biomechanical Stability of Acromioclavicular Joint

To measure the multiaxial stability of the acromioclavicular joint before and after transection of the acromioclavicular capsule and coracoclavicular ligaments and after sequential repair of acromioclavicular and coracoclavicular ligaments. Biomechanical testing was performed on fresh-frozen human cadaveric shoulders (N= 6). Translational and rotational stability in the vertical and horizontal planes was measured in intact specimens, after transecting the acromioclavicular and coracoclavicular ligaments, and after sequentially performing the following procedures: single-bundle coracoclavicular repair (CCR), modified Weaver-Dunn procedure (WD), and acromioclavicular stabilization (ACS). Resecting the acromioclavicular and coracoclavicular significantly reduced translational stiffness in the inferior and anteroposterior directions, as well as rotational stiffness about the vertical and anteroposterior axes. All 3 surgical procedures increased inferior translational stiffness relative to the intact condition (Intact: 38 ± 9 N/mm, CCR: 54 ± 23 N/mm (P = .03), CCR+WD 52 ± 20 N/mm (P= .07), CCR ± WD+ACS 50 ± 21 N/mm (P= .17)). However, the combination of CCR, modified WD, and ACS resulted in the greatest increase in stiffness in internal rotation (Intact: 12.5 ± 7.4 cNm/deg, CCR: 1.2 ± 1.1 cNm/deg, CCR+WD 7.2 ± 3.0 N∗m/deg [P= .023], CCR+WD+ACS 11.6 ± 4.9 cNm/deg [P= .055]). The cumulative stability of CCR, WD reconstruction, and ACS appears to be additive. Our findings provide a biomechanical justification for combining all three techniques. Biomechanical studies assessing the performance of various acromioclavicular repairs and reconstructions should therefore incorporate multiaxial testing in their protocols. Multiple points of fixation that provide multidirectional stability have the potential to improve clinical outcomes and reduce failure rates of acromioclavicular joint repair or stabilization.

Effects of the Temperature-Time Regime of Curing of Composite Patch on Repair Process Efficiency.

Repair procedures with the use of composite patches are considered to be the most effective among the current technologies of repair of the structures of various applications. In the process of moulding-on of a patch made of polymeric composite material by means of curing, technological stresses arise in the patch. Determination of residual technological stresses is a priority task for the modelling of the repair process. Reduction of residual stresses can be achieved by optimization of the mode of repair patch curing. For meeting this objective, the method for determination of technological stresses, which arise in the structure under repair in the process of curing of a composite patch, has been developed. The method takes into account the shrinkage, change in physico-mechanical characteristics, rheological processes occurring in the binder during moulding process, and determination of stresses in the structure under repair at any time. Therefore, premature failure of the repair joint at the stage of repair can be avoided. It is shown that the method adequately describes the level of deformations and stresses in the structure being repaired at the stage of heating and holding of the composite patch. Increase in the moulding temperature leads to a reduction in residual stresses in the structure under repair. However, current stresses at the stages of heating and temperature holding are increased significantly. Reliability of assumptions and developed method is confirmed by the comparison with the experimental data. The obtained experimental graph of total deformation of the composite patch allowed us to clearly determine the moment of residual stress occurrence in the structure under repair. This moment matches quite exactly (with the discrepancy not exceeding 5 min) the gel point determined analytically based on dependence of the degree of curing on the moulding mode. Consequently, the research together with the results previously obtained allows making an integrated choice of geometric parameters of the repair composite patch and temperature–time regime of its curing in order to ensure the specified level of strength and stiffness of the structure under repair.

Device-Based Enrichment of Knee Joint Synovial Cells to Drive MSC Chondrogenesis Without Prior Culture Expansion In Vitro: A Step Closer to 1-Stage Orthopaedic Procedures

Background: Synovial fluid (SF) mesenchymal stem cells (MSCs) are derived from the synovial membrane and have cartilage repair potential. Their current use in clinical practice is largely exploratory. As their numbers tend to be small, therapeutic procedures using MSCs typically require culture expansion. Previous reports indicate that the stem cell–mobilizing device (STEM device) intraoperatively increases SF-MSCs. Purpose: This study evaluated the chondrogenic potential of non–culture expanded synovium-mobilized MSCs and SF-microfragments obtained after enrichment using the STEM device and ascertained if device-mediated synovial membrane manipulation facilitated ongoing MSC release. Study Design: Controlled laboratory study. Methods: Two samples of aspiration fluid were collected intraoperatively before and after STEM device utilization from patients (n = 16) undergoing diagnostic or therapeutic knee arthroscopy. Human knee synovium (n = 5) was collected during total knee replacement, and a suspended culture was performed to assess the effect of the STEM device on ongoing MSC release. Colony forming unit–fibroblastic assays were used to determine the number of MSCs. Additionally, cytometric characterization of stromal and immune cells and chondrogenesis differentiation assay were performed without culture expansion. Filtered platelet concentrates were prepared using the HemaTrate system. Results: After STEM device use, a significant increase was evident in SF-MSCs (P = .03) and synovial fluid–resident synovial tissue microfragments (P = .03). In vitro–suspended synovium released significantly more MSCs following STEM device use than nonstimulated synovium (P = .01). The STEM device–released total cellular fraction produced greater in vitro chondrogenesis with significantly more glycosaminoglycans (GAGs; P < .0001) when compared with non–STEM device synovial fluid material. Nonexpanded SF-MSCs and SF-microfragments combined with autologous filtered platelet concentrate produced significantly more GAGs than the complete chondrogenic media (P < .0001). The STEM device–mobilized cells contained more M2 macrophage cells and fewer M1 cells. Conclusion: Non–culture expanded SF-MSCs and SF-microfragments had the potential to undergo chondrogenesis without culture expansion, which can be augmented using the STEM device with increased MSC release from manipulated synovium for several days. Although preliminary, these findings offer proof of concept toward manipulation of the knee joint environment to facilitate endogenous repair responses. Clinical Relevance: Although numbers were small, this study highlights 3 factors relevant to 1-stage joint repair using the STEM device: increased SF-MSCs and SF-microfragments and prolonged synovial release of MSCs. Joint repair strategies involving endogenous MSCs for cartilage repair without the need for culture expansion in a 1-stage procedure may be possible.

An ECHO of Cartilage: In Silico Prediction of Combinatorial Treatments to Switch Between Transient and Permanent Cartilage Phenotypes With Ex Vivo Validation.

A fundamental question in cartilage biology is: what determines the switch between permanent cartilage found in the articular joints and transient hypertrophic cartilage that functions as a template for bone? This switch is observed both in a subset of OA patients that develop osteophytes, as well as in cell-based tissue engineering strategies for joint repair. A thorough understanding of the mechanisms regulating cell fate provides opportunities for treatment of cartilage disease and tissue engineering strategies. The objective of this study was to understand the mechanisms that regulate the switch between permanent and transient cartilage using a computational model of chondrocytes, ECHO. To investigate large signaling networks that regulate cell fate decisions, we developed the software tool ANIMO, Analysis of Networks with interactive Modeling. In ANIMO, we generated an activity network integrating 7 signal transduction pathways resulting in a network containing over 50 proteins with 200 interactions. We called this model ECHO, for executable chondrocyte. Previously, we showed that ECHO could be used to characterize mechanisms of cell fate decisions. ECHO was first developed based on a Boolean model of growth plate. Here, we show how the growth plate Boolean model was translated to ANIMO and how we adapted the topology and parameters to generate an articular cartilage model. In ANIMO, many combinations of overactivation/knockout were tested that result in a switch between permanent cartilage (SOX9+) and transient, hypertrophic cartilage (RUNX2+). We used model checking to prioritize combination treatments for wet-lab validation. Three combinatorial treatments were chosen and tested on metatarsals from 1-day old rat pups that were treated for 6 days. We found that a combination of IGF1 with inhibition of ERK1/2 had a positive effect on cartilage formation and growth, whereas activation of DLX5 combined with inhibition of PKA had a negative effect on cartilage formation and growth and resulted in increased cartilage hypertrophy. We show that our model describes cartilage formation, and that model checking can aid in choosing and prioritizing combinatorial treatments that interfere with normal cartilage development. Here we show that combinatorial treatments induce changes in the zonal distribution of cartilage, indication possible switches in cell fate. This indicates that simulations in ECHO aid in describing pathologies in which switches between cell fates are observed, such as OA.

3D-bioprinted BMSC-laden biomimetic multiphasic scaffolds for efficient repair of osteochondral defects in an osteoarthritic rat model

Osteochondral defect repair in osteoarthritis (OA) remains an unsolved clinical problem due to the lack of enough seed cells in the defect and chronic inflammation in the joint. To address this clinical need, we designed a bone marrow-derived mesenchymal stem cell (BMSC)-laden 3D-bioprinted multilayer scaffold with methacrylated hyaluronic acid (MeHA)/polycaprolactone incorporating kartogenin and β-TCP for osteochondral defect repair within each region. BMSC-laden MeHA was designed to actively introduce BMSCs in situ, and diclofenac sodium (DC)-incorporated matrix metalloproteinase-sensitive peptide-modified MeHA was induced on the BMSC-laden scaffold as an anti-inflammatory strategy. BMSCs in the scaffolds survived, proliferated, and produced large amounts of cartilage-specific extracellular matrix in vitro. The effect of BMSC-laden scaffolds on osteochondral defect repair was investigated in an animal model of medial meniscectomy-induced OA. BMSC-laden scaffolds facilitated chondrogenesis by promoting collagen II and suppressed interleukin 1β in osteochondral defects of the femoral trochlea. Congruently, BMSC-laden scaffolds significantly improved joint function of the injured leg with respect to the ground support force, paw grip force, and walk gait parameters. Therefore, this research demonstrates the potential of 3D-bioprinted BMSC-laden scaffolds to simultaneously inhibit joint inflammation and promote cartilage defect repair in OA joints.

Integrated Osteochondral Microsphere Scaffolds with Biomimetic Architecture and Regional Vascularization for Joint Repair

Osteochondral lesion potentially causes a variety of joint degenerative diseases if it cannot be treated effectively and timely. Microfracture as the first line surgical choice achieves limited results for the larger defect whereas cartilage patches trigger integrated instability and cartilage fibrosis. To tackle aforementioned issues, here we explore to construct an integrated osteochondral scaffold for synergetic regeneration of cartilage and subchondral bone in one system. On the macro level, we fabricated three integrated scaffolds with distinct channel structure of Non-channel, Consecutive-channel and Inconsecutive-channel via Selective Laser Sintering (SLS). On the micro level, cartilage zone and subchondral bone zone of integrated scaffold consisted of small polycaprolactone (PCL) microspheres with the diameter of 50 μm and large PCL microspheres with the diameter of 150 μm, respectively. As a result, cartilage zone exhibited a dense phase for the inhibition of vessel invasion while subchondral zone generated a porous phase for the ingrowth of bone and vessel. Our findings showed that Inconsecutive-channel scaffolds possessed biomimetic hierarchical structure, adequate mechanical properties, gradient interconnected porosity in comparison with Non-channel and Consecutive-channel groups. Moreover, Inconsecutive-channel scaffolds obviously induced cartilage regeneration and subchondral bone remodeling. Consequently, this work not only achieves an effective and regeneratable microsphere scaffold for osteochondral reconstruction, but also provides a feasible methodology to recover injured joint through integrated design pattern. Funding Information: This work was financially supported by the National Key Research and Development Program of China (2017YFC1103900), the National Natural Science Foundation of China (32171323, 91939111), Key Research and Development Program of Hubei Province (2020BCB056), International Science and Technology Cooperation Projects of Shenzhen (GJHZ20200731095211035), Sanming Project of Medicine in Shenzhen (SZSM201812055), and the Fundamental Research Funds for the Central Universities (2019kfyRCPY103). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All procedures for animal experiments were approved by the Institutional Animal Care and Use Committee of Huazhong University of Science and Technology (SYXK20170094).

Autologous chondrocyte implantation combined with anterior cruciate ligament reconstruction: similar short-term results in comparison with isolated cartilage repair in ligament intact joints

PurposeBoth acute ruptures of the anterior cruciate ligament (ACL) as well as chronic ACL insufficiency show a high association with focal cartilage defects of the knee. However, the results after combined ACL reconstruction and cartilage repair are not well investigated. The aim of the present study was to investigate the short-term outcomes after autologous chondrocyte implantation (ACI) in combination with ACL reconstruction and to compare the results with patients who underwent isolated ACI in ligament intact knees.MethodsAll patients who were registered in the German Cartilage Registry with ACI for focal cartilage defects in the knee joint in combination with ACL reconstruction and who completed the 24 month follow-up were included in the study group. A matched-pair procedure according to gender, defect location, defect size, and age was used to create a control group of patients with isolated ACI in ACL intact joints. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the numeric analog scale for pain (NAS) were used to assess the preoperative state as well as the clinical outcomes 12 and 24 months after surgery.ResultsA total of 34 patients were included in both the study group (age mean 33.3 ± SD 8.8 years) and the control group (33.6 ± 8.4 years) with a median defect size of 466 (25%-75% IQR 375–600) mm2 and 425 (IQR 375–600) mm2, respectively. In comparison with the preoperative state (median 67, IQR 52–75), the study group showed a significant increase of the total KOOS after 12 months (78, IQR 70–86; p = 0.014) and after 24 months (81, IQR 70–84; p = 0.001). The NAS for pain did not change significantly in the postoperative course. In comparison with the control group there was no significant difference for the total KOOS neither preoperative (control group median 67, IQR 52–73) nor at any postoperative time point (12 months: 82, IQR 67–93; 24 months: 81, IQR 71–91).ConclusionThe clinical short-term outcomes after ACI at the knee joint in combination with ACL reconstruction are good and similar to the results after isolated ACI in ligament intact knees.Level of evidenceIII.

Joint distraction for osteoarthritis: clinical evidence and molecular mechanisms.

Joint distraction, the prolonged mechanical separation of the bones at a joint, has emerged as a joint-preserving treatment for end-stage osteoarthritis, with the gradually growing promise of implementation in regular clinical practice. Joint distraction of the knee has been most extensively studied, with these studies showing prolonged symptomatic improvement in combination with repair of cartilage tissue in degenerated knee joints, supporting the concept that cartilage repair can translate into real clinical benefit. The reversal of tissue degeneration observed with joint distraction could be the result of one or a combination of various proposed mechanisms, including partial unloading, synovial fluid pressure oscillation, mechanical and biochemical changes in subchondral bone, adhesion and chondrogenic commitment of joint-derived mesenchymal stem cells or a change in the molecular milieu of the joint. The overall picture that emerges from the combined evidence is relevant for future research and treatment-related improvements of joint distraction and for translation of the insights gained about tissue repair to other joint-preserving techniques. It remains to be elucidated whether optimizing the biomechanical conditions during joint distraction can actually cure osteoarthritis rather than only providing temporary symptomatic relief, but even temporary relief might be relevant for society and patients, as it will delay joint replacement with a prosthesis at an early age and thereby avert revision surgery later in life. Most importantly, improved insights into the underlying mechanisms of joint repair might provide new leads for more targeted treatment options.