1. Direct injury to skeletal muscle results in fragmentation and necrosis of muscle fibres, though this is patchy in distribution. 2. The sarcolemmal basement membranes form the interface along which fibre regeneration takes place. 3. Phagocytosis of disorganised sarcoplasm is an essential prelude to the reconstitution of severely damaged fibres. 4. Regeneration of injured muscle begins with proliferation of basophilic cells probably originating from muscle satellite cells. After a few days typical myoblast nuclear chains are present. By a week following injury the chains of myoblasts have formed myotubes, which possess myofibrils and sarcomeres. 5. By twelve days in the monkey and by eighteen days in man the muscle fibre regenerative process shows many new fibres which have not reached a mature diameter. 6. Much collagen may be formed in the tissue space at the site of injury. It appears that as the muscle fibres increase in diameter the collagen decreases in extent. 7. In the monkey by three weeks the muscle at the fracture site appears normal. This is also true in the specimens examined at four, six and twelve weeks. 8. In the monkeys the injured limb was immediately used to run and jump. A parallel intense and early activity of muscle and joints was a cardinal point in the management of this series of fracture patients. The clinical results were satisfactory. 9. It is concluded that in both the monkey and in man, given active limb movements, permanent and functionally useful muscle regeneration occurs following soft-tissue injury associated with a bone fracture

MicroRNAs (miRNAs) are a class of small non-coding RNAs that have emerged as potential predictive, prognostic, and therapeutic biomarkers, relevant to many pathophysiological conditions including limb immobilization, osteoarthritis, sarcopenia, and cachexia. Impaired musculoskeletal homeostasis leads to distinct muscle atrophies. Understanding miRNA involvement in the molecular mechanisms underpinning conditions such as muscle wasting may be critical to developing new strategies to improve patient management. MicroRNAs are powerful post-transcriptional regulators of gene expression in muscle and, importantly, are also detectable in the circulation. MicroRNAs are established modulators of muscle satellite stem cell activation, proliferation, and differentiation, however, there have been limited human studies that investigate miRNAs in muscle wasting. This narrative review summarizes the current knowledge as to the role of miRNAs in the skeletal muscle differentiation and atrophy, synthesizing the findings of published data.

Cite this article: Bone Joint Res 2020;9(11):798–807.

Aims

Cartilage injuries rarely heal spontaneously and often require surgical intervention, leading to the formation of biomechanically inferior fibrous tissue. This study aimed to evaluate the possible effect of amelogenin on the healing process of a large osteochondral injury (OCI) in a rat model.

A child with traumatic laceration of the tendo Achillis developed secondary infection after primary repair. This resulted in the loss of 5 cm of the distal part of the tendon and overlying soft tissue. The patient was treated with a free skin flap to cover the wound and to control the infection leaving reconstruction for a second-stage procedure.

However, when he was assessed two years after the skin-flap, delayed reconstruction proved to be unnecessary since he had regained normal ankle function spontaneously and could demonstrate equal function in both tendons.

1. The characteristics of the regenerated knee meniscus are reviewed.

2. A case is reported in which a meniscus twice regenerated and was twice torn.

1 . The repair of a simple crush injury was studied in rats, in both normally innervated and completely denervated muscle. In each case the histological findings at periods from two hours to thirty-two weeks are described.

2. The denervated muscle showed active and effective repair.

3. A comparison with the findings in normally innervated muscle establishes that the cellular processes of repair do not depend on connections with the central nervous system.

The effect of cortisone on the repair of simple muscle injury was studied in rabbits. The histological findings in the crushed muscle are described for a period up to twenty-one days after injury.

Cortisone defers the onset of muscle regeneration, and retards its progress, but it does not change the course of the repair process or alter its eventual outcome under the conditions of the experiment.

This apparent refractoriness of repair of muscle, as compared with that of other connective tissues, is discussed.

We reviewed three infants with destructive osteomyelitis involving the proximal tibial epiphysis at a follow-up of eight to 22 years. All cases showed early radiographic destructive changes in the medial or lateral aspects of the epiphysis and metaphysis. Despite the ominous early appearance of the epiphysis, all cases showed spontaneous re-ossification of the epiphysis with restoration of the tibial condyle and preservation of joint congruity. The patients, however, developed a valgus or varus deformity which was treated satisfactorily with one to three proximal tibial osteotomies. The potential for regeneration of the epiphysis following infantile osteomyelitis of the proximal tibia suggests these cases should be treated expectantly with regard to joint congruity.

A 16-year-old boy was involved in an agricultural accident in which he sustained a large wound to the right arm and forearm. Radiological examination showed loss of the distal half of the humerus. A posterior splint was applied and after two months there was regeneration of the distal humerus including the articular portion. He was able to use his arm at five months. Twenty years later, he had a painless elbow and a 70° range of movement.

An orientated substratum has been implicated in the development and regeneration of axons and synapses. We prepared a basement membrane matrix from autogenous striated muscle, used it to repair the sciatic nerve in rats, then investigated the results by histology and electrophysiology. When treated grafts were coaxially aligned with the nerve fascicles functional recovery appeared within 30 days, with good growth of axons into the distal nerve. Grafts with myotubes at right angles to the nerve fascicles supported nerve regeneration but at a slower rate. Grafts of coaxially aligned but untreated muscle allowed axon penetration only through naturally degenerated muscle fibres, with minimal axon penetration of the distal nerve. It is concluded that in the rat a treated graft with correctly orientated empty myotubes can facilitate and guide the regeneration of peripheral nerve after injury and so lead to recolonisation of the distal stump with functional recovery.

We describe a three-year-old boy who had spontaneous regeneration of the entire lateral malleolus after injury, including the epiphysis, physis and metaphysis.

Little is known of the effects of synovectomy on articular cartilage. In order to investigate this matter, anterior synovectomy of the knee was performed in thirty-five normal adult rabbits and in thirty-five which were given 25 milligrams of hydrocortisone intramuscularly each week afterwards. The animals were killed at intervals from four to 110 days after synovectomy. Histological examination of the regenerating synovium in both groups showed complete structural and functional regeneration by eighty days in the first group and a delay in regeneration in the steroid group. ³⁵Sulphur autoradiographs of the articular cartilage of femoral and tibial condyles revealed surface fibrillation and chondrocyte death in 23 per cent of normal knees after eighty days but only 1·8 per cent of knees of animals receiving hydrocortisone. Thus synovectomy in a healthy joint may have an unfavourable effect on the physiology of cartilage by alteration of synovial composition and hyaluronate content in normal joints. Systemically-administered hydrocortisone may reduce this harmful effect in normal cartilage.

1. A clinico-pathological study of a patient who suffered traumatic rupture of his right popliteal artery is outlined.

2. Collateral circulation from the genicular anastomosis developed within twenty hours.

3. Ischaemic necrosis of the belly of the tibialis anterior occurred, but voluntary power began to return about twenty-one weeks after injury.

4. Biopsy of the muscle nineteen, fifty-seven and seventy-six weeks after injury showed that the muscle belly was being reconstituted by new fibres and that the ischaemic tissue remained entombed in the deepest part of the muscle. The regenerating fibres arose from small numbers of subfascial fibres which either survived the ischaemic episode or had arisen by myoblastic differentiation of connective tissue cells. Sarcoplasmic outgrowths produced new contractile substance, and new fibres were formed by amitotic fission. Many of the fibres matured and the regenerative process was still active seventy-six weeks after injury.

5. Growth of new nerve bundles containing myelinated axons accompanied the development of new muscle fibres.

Aims. Implantation of ultra-purified alginate (UPAL) gel is safe and effective in animal osteochondral defect models. This study aimed to examine the applicability of UPAL gel implantation to acellular therapy in humans with cartilage injury. Methods. A total of 12 patients (12 knees) with symptomatic, post-traumatic, full-thickness cartilage lesions (1.0 to 4.0 cm. 2. ) were included in this study. UPAL gel was implanted into chondral defects after performing bone marrow stimulation technique, and assessed for up to three years postoperatively. The primary outcomes were the feasibility and safety of the procedure. The secondary outcomes were self-assessed clinical scores, arthroscopic scores, tissue biopsies, and MRI-based estimations. Results. No obvious adverse events related to UPAL gel implantation were observed. Self-assessed clinical scores, including pain, symptoms, activities of daily living, sports activity, and quality of life, were improved significantly at three years after surgery. Defect filling was confirmed using second-look arthroscopy at 72 weeks. Significantly improved MRI scores were observed from 12 to 144 weeks postoperatively. Histological examination of biopsy specimens obtained at 72 weeks after implantation revealed an extracellular matrix rich in glycosaminoglycan and type II collagen in the reparative tissue. Histological assessment yielded a mean overall International Cartilage Regeneration & Joint Preservation Society II score of 69.1 points (SD 10.4; 50 to 80). Conclusion. This study provides evidence supporting the safety of acellular UPAL gel implantation in facilitating cartilage repair. Despite being a single-arm study, it demonstrated the efficacy of UPAL gel implantation, suggesting it is an easy-to-use, one-step method of cartilage tissue repair circumventing the need to harvest donor cells. Cite this article: Bone Joint J 2023;105-B(8):880–887

Aims. The aim of this study was to evaluate the association between chondral injury and interval from anterior cruciate ligament (ACL) tear to surgical reconstruction (ACLr). Methods. Between January 2012 and January 2022, 1,840 consecutive ACLrs were performed and included in a single-centre retrospective cohort. Exclusion criteria were partial tears, multiligament knee injuries, prior ipsilateral knee surgery, concomitant unicompartmental knee arthroplasty or high tibial osteotomy, ACL agenesis, and unknown date of tear. A total of 1,317 patients were included in the final analysis, with a median age of 29 years (interquartile range (IQR) 23 to 38). The median preoperative Tegner Activity Score (TAS) was 6 (IQR 6 to 7). Patients were categorized into four groups according to the delay to ACLr: < three months (427; 32%), three to six months (388; 29%), > six to 12 months (248; 19%), and > 12 months (254; 19%). Chondral injury was assessed during arthroscopy using the International Cartilage Regeneration and Joint Preservation Society classification, and its association with delay to ACLr was analyzed using multivariable analysis. Results. In the medial compartment, delaying ACLr for more than 12 months was associated with an increased rate (odds ratio (OR) 1.93 (95% confidence interval (CI) 1.27 to 2.95); p = 0.002) and severity (OR 1.23 (95% CI 1.08 to 1.40); p = 0.002) of chondral injuries, compared with < three months, with no association in patients aged > 50 years old. No association was found for shorter delays, but the overall dose-effect analysis was significant for the rate (p = 0.015) and severity (p = 0.026) of medial chondral injuries. Increased TAS was associated with a significantly reduced rate (OR 0.88 (95% CI 0.78 to 0.99); p = 0.036) and severity (OR 0.96 (95% CI 0.92 to 0.99); p = 0.017) of medial chondral injuries. In the lateral compartment, no association was found between delay and chondral injuries. Conclusion. Delay was associated with an increased rate and severity of medial chondral injuries in a dose-effect fashion, in particular for delays > 12 months. Younger patients seem to be at higher risk of chondral injury when delaying surgery. The timing of ACLr should be optimally reduced in this population. Cite this article: Bone Joint J 2023;105-B(9):953–960

Aims. Successful cell therapy in hip osteonecrosis (ON) may help to avoid ON progression or total hip arthroplasty (THA), but the achieved bone regeneration is unclear. The aim of this study was to evaluate amount and location of bone regeneration obtained after surgical injection of expanded autologous mesenchymal stromal cells from the bone marrow (BM-hMSCs). Methods. A total of 20 patients with small and medium-size symptomatic stage II femoral head ON treated with 140 million BM-hMSCs through percutaneous forage in the EudraCT 2012-002010-39 clinical trial were retrospectively evaluated through preoperative and postoperative (three and 12 months) MRI. Then, 3D reconstruction of the original lesion and the observed postoperative residual damage after bone regeneration were analyzed and compared per group based on treatment efficacy. Results. The mean preoperative lesion volume was 18.7% (SD 10.2%) of the femoral head. This reduced to 11.6% (SD 7.5%) after three months (p = 0.015) and 3.7% (SD 3%) after one year (p < 0.001). Bone regeneration in healed cases represented a mean 81.2% (SD 13.8%) of the initial lesion volume at one year. Non-healed cases (n = 1 stage progression; n = 3 THAs) still showed bone regeneration but this did not effectively decrease the ON volume. A lesion size under mean 10% (SD 6%) of the femoral head at three months predicted no ON stage progression at one year. Regeneration in the lateral femoral head (C2 under Japanese Investigation Committee (JCI) classification) and in the central and posterior regions of the head was predominant in cases without ON progression. Conclusion. Bone regeneration was observed in osteonecrotic femoral heads three months after expanded autologous BM-hMSC injection, and the volume and location of regeneration indicated the success of the therapy. Cite this article: Bone Joint Res 2022;11(12):881–889

Aims. The aim of this retrospective study was to determine if there are differences in short-term clinical outcomes among four different types of matrix-associated autologous chondrocyte transplantation (MACT). Methods. A total of 88 patients (mean age 34 years (SD 10.03), mean BMI 25 kg/m. 2. (SD 3.51)) with full-thickness chondral lesions of the tibiofemoral joint who underwent MACT were included in this study. Clinical examinations were performed preoperatively and 24 months after transplantation. Clinical outcomes were evaluated using the International Knee Documentation Committee (IKDC) Subjective Knee Form, the Brittberg score, the Tegner Activity Scale, and the visual analogue scale (VAS) for pain. The Kruskal-Wallis test by ranks was used to compare the clinical scores of the different transplant types. Results. The mean defect size of the tibiofemoral joint compartment was 4.28 cm. 2. (SD 1.70). In total, 11 patients (12.6%) underwent transplantation with Chondro-Gide (matrix-associated autologous chondrocyte implantation (MACI)), 40 patients (46.0%) with Hyalograft C (HYAFF), 21 patients (24.1%) with Cartilage Regeneration System (CaReS), and 15 patients (17.2%) with NOVOCART 3D. The mean IKDC Subjective Knee Form score improved from 35.71 (SD 6.44) preoperatively to 75.26 (SD 18.36) after 24 months postoperatively in the Hyalograft group, from 35.94 (SD 10.29) to 71.57 (SD 16.31) in the Chondro-Gide (MACI) group, from 37.06 (SD 5.42) to 71.49 (SD 6.76) in the NOVOCART 3D group, and from 45.05 (SD 15.83) to 70.33 (SD 19.65) in the CaReS group. Similar improvements were observed in the VAS and Brittberg scores. Conclusion. Two years postoperatively, there were no significant differences in terms of outcomes. Our data demonstrated that MACT, regardless of the implants used, resulted in good clinical improvement two years after transplantation for localized tibiofemoral defects. Cite this article: Bone Joint Res 2021;10(7):370–379