Fibronectin matrix assembly and TGFß1 presentation for chondrogenesis of patient derived pericytes for microtia repair.

Tissue engineered cartilage for external ear reconstruction of congenital deformities, such as microtia or resulting from trauma, remains a significant challenge for plastic and reconstructive surgeons. Current strategies involve harvesting autologous costal cartilage or expanding autologous chondrocytes ex vivo. However, these procedures often lead to donor site morbidity and a cell source with limited expansion capacity. Stromal stem cells such as perivascular stem cells (pericytes) offer an attractive alternative cell source, as they can be isolated from many human tissues, readily expanded in vitro and possess chondrogenic differentiation potential. Here, we successfully isolate CD146+ pericytes from the microtia remnant from patients undergoing reconstructive surgery (Microtia pericytes; MPs). Then we investigate their chondrogenic potential using the polymer poly(ethyl acrylate) (PEA) to unfold the extracellular matrix protein fibronectin (FN). FN unfolding exposes key growth factor (GF) and integrin binding sites on the molecule, allowing tethering of the chondrogenic GF transforming growth factor beta 1 (TGFß1). This system leads to solid-phase, matrix-bound, GF presentation in a more physiological-like manner than that of typical chondrogenic induction media (CM) formulations that tend to lead to off-target effects. This simple and controlled material-based approach demonstrates similar chondrogenic potential to CM, while minimising proclivity toward hypertrophy, without the need for complex induction media formulations.

Deciphering Mesenchymal Drivers of Human Dupuytren's Disease at Single-Cell Level.

Dupuytren's disease (DD) is a common, progressive fibroproliferative disease affecting the palmar fascia of the hands, causing fingers to irreversibly flex toward the palm with significant loss of function. Surgical treatments are limited; therefore, effective new therapies for DD are urgently required. To identify the key cellular and molecular pathways driving DD, we employed single-cell RNA sequencing, profiling the transcriptomes of 35,250 human single cells from DD, nonpathogenic fascia, and healthy dermis. We identify a DD-specific population of pathogenic PDPN+/FAP+ mesenchymal cells displaying an elevated expression of fibrillar collagens and profibrogenic genes. In silico trajectory analysis reveals resident fibroblasts to be the source of this pathogenic population. To resolve the processes governing DD progression, genes differentially expressed during fibroblast differentiation were identified, including upregulated TNFRSF12A and transcription factor SCX. Knockdown of SCX and blockade of TNFRSF12A inhibited the proliferation and altered the profibrotic gene expression of cultured human FAP+ mesenchymal cells, demonstrating a functional role for these genes in DD. The power of single-cell RNA sequencing is utilized to identify the major pathogenic mesenchymal subpopulations driving DD and the key molecular pathways regulating the DD-specific myofibroblast phenotype. Using this precision medicine approach, inhibition of TNFRSF12A has shown potential clinical utility in the treatment of DD.

The Value of the Distal Radioulnar Joint Effusion in Diagnosing Triangular Fibrocartilage Complex Tears on Magnetic Resonance Imaging.

BACKGROUND: A retrospective study was conducted to evaluate the role of distal radioulnar joint (DRUJ) effusion in aiding the diagnostic accuracy of central triangular fibrocartilage complex (TFCC) tears on non-contrast MRI. METHODS: 89 consecutive patients who had undergone wrist arthroscopy for ulna sided wrist pain in our unit were identified and their preoperative imaging reviewed. Two consultant musculoskeletal Radiologists independently reported the presence or absence of a DRUJ effusion and or a TFCC tear. The inter-observer variability was calculated using weighted Kappa tests. Two by two tables were constructed to calculate the sensitivity and specificity of reported TFCC tear or DRUJ effusion on MRI in correctly diagnosing central TFCC tears identified at arthroscopy. RESULTS: Sensitivity of MRI to report a TFCC tear was 0.56 and specificity was 0.79. Sensitivity increased to 0.89 if either a DRUJ effusion or TFCC tear were seen on MRI. When observed together, the presence of both a DRUJ effusion and a TFCC tear seen on the imaging lead to a sensitivity of 0.74 and PPV of 82% when compared to findings at arthroscopy. In the absence of both DRUJ effusion and TFCC tear, the specificity of MRI increased to 0.92. Agreement by the radiologists on the presence of DRUJ effusion was substantial (k value 0.67) and TFCC tear was moderate (k value 0.58). CONCLUSION: The presence of DRUJ effusion on MRI can further improve sensitivity of MRI in diagnosing central TFCC tears. The sensitivity of detecting a central TFCC tear on MRI scan when both a DRUJ effusion and a TFCC tear were seen (0.74) is comparable to rates demonstrated on MRA meta-analysis results (0.78). Furthermore, considering the absence of both a DRUJ effusion and TFCC tear seen on MRI is useful in excluding the presence of a TFCC tear at arthroscopy.

The Role of Selective Peripheral Neurectomy in the Treatment of Upper Limb Spasticity.

BACKGROUND: Management of upper limb spasticity remains challenging. Selective peripheral neurectomy (SPN) is a relatively recent intervention for cases refractory to medical therapy. The aim of this study was to conduct a systematic review looking at the efficacy and outcomes of SPN, in order to clarify the patient selection criteria and surgical technique. METHODS: A search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science Core Collection, Open Grey and CINAHL was conducted. Inclusion criteria included studies comparing pre- and post-operative outcomes for SPN, neurectomy, fasciculotomy and upper limb spasticity. RESULTS: Only case series were reported with no randomised controlled trials found. 7 studies met the inclusion criteria with a total of 174 patients. A meta-analysis was not possible due to the degree of baseline heterogeneity. All studies had no control arm for comparison of outcomes, with a high risk of bias due to poor internal and external validity, as well as design and performance bias. Surgical techniques differ vastly between studies, with percentage of fascicles ablated between 30-80% and length of neurectomy between 5-10 mm. Some advocated removing end branches while others performed fascicular SPN proximally. 13 patients underwent orthopaedic or neurosurgical procedures, which are both confounding factors. All studies reported an improvement in spasticity although functional outcomes were reported with non-standardized measures. Recurrence rates were reported to be 0-16.1% (mean 3.72%). CONCLUSIONS: From this systematic review, SPN appeared to be a useful technique in selected cases, but overall no firm conclusions can be drawn regarding the best surgical technique, or the extent of functional improvement.