Single-cell resolution of MET- and EMT-like programs in osteoblasts during zebrafish fin regeneration.

Zebrafish regenerate fin rays following amputation through epimorphic regeneration, a process that has been proposed to involve the epithelial-to-mesenchymal transition (EMT). We performed single-cell RNA sequencing (scRNA-seq) to elucidate osteoblastic transcriptional programs during zebrafish caudal fin regeneration. We show that osteoprogenitors are enriched with components associated with EMT and its reverse, mesenchymal-to-epithelial transition (MET), and provide evidence that the EMT markers cdh11 and twist2 are co-expressed in dedifferentiating cells at the amputation stump at 1 dpa, and in differentiating osteoblastic cells in the regenerate, the latter of which are enriched in EMT signatures. We also show that esrp1, a regulator of alternative splicing in epithelial cells that is associated with MET, is expressed in a subset of osteoprogenitors during outgrowth. This study provides a single cell resource for the study of osteoblastic cells during zebrafish fin regeneration, and supports the contribution of MET- and EMT-associated components to this process.

Radiologic Guide to Surgical Treatment of Kienbock's Disease.

Kienbock's disease, or avascular necrosis of the lunate, is a progressive disease ultimately resulting in end-stage arthrosis of the wrist. Various surgical treatments are available for different Lichtman stages of disease. We review the surgical options and indications, expected radiologic post-operative appearance, as well as detail potential surgical complications, as they relate to Kienbock's disease.

Looking Ahead to Engineering Epimorphic Regeneration of a Human Digit or Limb.

Approximately 2 million people have had limb amputations in the United States due to disease or injury, with more than 185,000 new amputations every year. The ability to promote epimorphic regeneration, or the regrowth of a biologically based digit or limb, would radically change the prognosis for amputees. This ambitious goal includes the regrowth of a large number of tissues that need to be properly assembled and patterned to create a fully functional structure. We have yet to even identify, let alone address, all the obstacles along the extended progression that limit epimorphic regeneration in humans. This review aims to present introductory fundamentals in epimorphic regeneration to facilitate design and conduct of research from a tissue engineering and regenerative medicine perspective. We describe the clinical scenario of human digit healing, featuring published reports of regenerative potential. We then broadly delineate the processes of epimorphic regeneration in nonmammalian systems and describe a few mammalian regeneration models. We give particular focus to the murine digit tip, which allows for comparative studies of regeneration-competent and regeneration-incompetent outcomes in the same animal. Finally, we describe a few forward-thinking opportunities for promoting epimorphic regeneration in humans.

Diagnosis and Treatment of Work-Related Ulnar Neuropathy at the Elbow.

Ulnar neuropathy at the elbow (UNE) is the second most common entrapment neuropathy after carpal tunnel syndrome and occurs most commonly at the elbow due to mechanical forces that produce traction or ischemia to the nerve. The primary symptom associated with UNE is diminished sensation or dysesthesias in the fourth or fifth digits, often coupled with pain in the proximal medial aspect of the elbow. Treatment may be conservative or surgical, but optimal management remains controversial. Surgery should include exploration of the ulnar nerve throughout its course around the elbow and release of all compressive structures.

Functional Outcomes Following Bridge Plate Fixation for Distal Radius Fractures.

PURPOSE: To determine the functional outcomes of patients treated with dorsal spanning distraction bridge plate fixation for distal radius fractures. METHODS: All adult patients at our institution who underwent treatment of a unilateral distal radius fracture using a dorsal bridge plate from 2008 to 2012 were identified retrospectively. Patients were enrolled in clinical follow-up to assess function. Wrist range of motion, grip strength, and extension torque were measured systematically and compared with the contralateral, uninjured wrist. Patients also completed Quick-Disabilities of the Arm, Shoulder, and Hand and Patient-Rated Wrist Evaluation outcomes questionnaires. RESULTS: Eighteen of 100 eligible patients, with a minimum of 1 year from the time of implant removal, were available for follow-up (mean, 2.7 y). All fracture patterns were comminuted and intra-articular (AO 23.C3). There were significant decreases in wrist flexion (43° vs 58°), extension (46° vs 56°), and ulnar deviation (23° vs 29°) compared with the contralateral uninjured wrist. Grip strength was 86% and extension torque was 78% of the contralateral wrist. Comparison of dominant and nondominant wrist injuries identified nearly complete recovery of grip (95%) and extension (96%) strength of dominant-sided wrist injuries, compared with grip (79%) and extension (65%) strength in those with an injured nondominant wrist. Mean Quick-Disabilities of the Arm, Shoulder, and Hand and Patient-Rated Wrist Evaluation scores were 16 and 14, respectively. There were 2 cases of postoperative surgical site pain and no cases of infection, tendonitis, or tendon rupture. CONCLUSIONS: Distraction bridge plate fixation for distal radius fractures is safe with minimal complications. Functional outcomes are similar to those published for other treatment methods. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Modeling Implantable Passive Mechanisms for Modifying the Transmission of Forces and Movements Between Muscle and Tendons.

This paper explores the development of biomechanical models for evaluating a new class of passive mechanical implants for orthopedic surgery. The proposed implants take the form of passive engineered mechanisms, and will be used to improve the functional attachment of muscles to tendons and bone by modifying the transmission of forces and movement inside the body. Specifically, we present how two types of implantable mechanisms may be modeled in the open-source biomechanical software OpenSim. The first implant, which is proposed for hand tendon-transfer surgery, differentially distributes the forces and movement from one muscle across multiple tendons. The second implant, which is proposed for knee-replacement surgery, scales up the forces applied to the knee joint by the quadriceps muscle. This paper's key innovation is that such mechanisms have never been considered before in biomechanical simulation modeling and in surgery. When compared with joint function enabled by the current surgical practice of using sutures to make the attachment, biomechanical simulations show that the surgery with 1) the differential mechanism (tendon network) implant improves the fingers' ability to passively adapt to an object's shape significantly during grasping tasks (2.74× as measured by the extent of finger flexion) for the same muscle force, and 2) the force-scaling implant increases knee-joint torque by 84% for the same muscle force. The critical significance of this study is to provide a methodology for the design and inclusion of the implants into biomechanical models and validating the improvement in joint function they enable when compared with current surgical practice.

Implanted passive engineering mechanism improves hand function after tendon transfer surgery: a cadaver-based study.

PURPOSE: The purpose of this study was to investigate if a new tendon transfer surgical procedure that uses an implanted passive engineering mechanism for attaching multiple tendons to a single donor muscle in place of directly suturing the tendons to the muscle improves hand function in physical interaction tasks such as grasping. METHODS: The tendon transfer surgery for high median ulnar palsy was used as an exemplar, where all four flexor digitorum profundus (FDP) tendons are directly sutured to the extensor carpi radialis longus (ECRL) muscle to restore flexion. The new procedure used a passive hierarchical artificial pulley system to connect the muscle to the tendons. Both the suture-based and pulley-based procedures were conducted on N = 6 cadaver hands. The fingers' ability to close around four objects when the ECRL tendon was pulled was tested. Post-surgery hand function was evaluated based on the actuation force required to create a grasp and the slip between the fingers and the object after the grasp was created. RESULTS: When compared with the suture-based procedure, the pulley-based procedure (i) reduced the actuation force required to close all four fingers around the object by 45 % and (ii) improved the fingers' individual adaptation to the object's shape during the grasping process and reduced slip by 52 % after object contact (2.99° ± 0.28° versus 6.22° ± 0.66°). CONCLUSIONS: The cadaver study showed that the implanted engineering mechanism for attaching multiple tendons to one muscle significantly improved hand function in grasping tasks when compared with the current procedure.

Botulinum toxin induces muscle paralysis and inhibits bone regeneration in zebrafish.

Intramuscular administration of Botulinum toxin (BTx) has been associated with impaired osteogenesis in diverse conditions of bone formation (eg, development, growth, and healing), yet the mechanisms of neuromuscular-bone crosstalk underlying these deficits have yet to be identified. Motivated by the emerging utility of zebrafish (Danio rerio) as a rapid, genetically tractable, and optically transparent model for human pathologies (as well as the potential to interrogate neuromuscular-mediated bone disorders in a simple model that bridges in vitro and more complex in vivo model systems), in this study, we developed a model of BTx-induced muscle paralysis in adult zebrafish, and we examined its effects on intramembranous ossification during tail fin regeneration. BTx administration induced rapid muscle paralysis in adult zebrafish in a manner that was dose-dependent, transient, and focal, mirroring the paralytic phenotype observed in animal and human studies. During fin regeneration, BTx impaired continued bone ray outgrowth, morphology, and patterning, indicating defects in early osteogenesis. Further, BTx significantly decreased mineralizing activity and crystalline mineral accumulation, suggesting delayed late-stage osteoblast differentiation and/or altered secondary bone apposition. Bone ray transection proximal to the amputation site focally inhibited bone outgrowth in the affected ray, implicating intra- and/or inter-ray nerves in this process. Taken together, these studies demonstrate the potential to interrogate pathological features of BTx-induced osteoanabolic dysfunction in the regenerating zebrafish fin, define the technological toolbox for detecting bone growth and mineralization deficits in this process, and suggest that pathways mediating neuromuscular regulation of osteogenesis may be conserved beyond established mammalian models of bone anabolic disorders.

Imaging key wrist ligaments: what the surgeon needs the radiologist to know.

OBJECTIVE: Although much attention is paid to the scapholunate ligament, lunotriquetral ligament, and the triangular fibrocartilage complex, additional intrinsic and extrinsic ligaments in the wrist play an important part in carpal stability. With improved MRI techniques, the radiologist can increasingly visualize these ligaments. CONCLUSION: The anatomy, MRI appearance, and clinical significance of the scapholunate ligament, lunotriquetral ligament, triangular fibrocartilage complex, carpal metacarpal ligaments, and volar and dorsal extrinsic ligaments are reviewed.

Complications associated with distraction plate fixation of wrist fractures.

This article discusses the major and minor complications of distal plating in the light of a cohort study carried out by the authors, who reviewed all patients undergoing bridge distraction plate fixation of distal radius fractures by three surgeons in a single level I trauma center. The article discusses the effectiveness and the complication rates associated with the technique.

Mammalian regeneration and regenerative medicine.

Mammals are generally considered to be poor regenerators, yet there are a handful of mammalian models that display a robust ability to regenerate. One such system is the regenerating tips of digits in both humans and mice. In vitro studies of regenerating fetal human and mouse digit tips display both anatomical and molecular similarities, indicating that the mouse digit is a clinically relevant model. At the same time, genetic studies on mouse digit tip regeneration have identified signaling pathways required for the regeneration response that parallel those known to be important for regeneration in lower vertebrates. In addition, recent studies establish that digit tip regeneration involves the formation of a blastema that shares similarities with the amphibian blastema, thus establishing a conceptual bridge between clinical application and basic research in regeneration. In this review we discuss how the study of endogenous regenerating mammalian systems is enhancing our understanding of regenerative mechanisms and helping to shed light on the development of therapeutic strategies in regenerative medicine.

Development and regeneration of the neonatal digit tip in mice.

The digit tips of children and rodents are known to regenerate following amputation. The skeletal structure that regenerates is the distal region of the terminal phalangeal bone that is associated with the nail organ. The terminal phalanx forms late in gestation by endochondral ossification and continues to elongate until sexual maturity (8 weeks of age). Postnatal elongation at its distal end occurs by appositional ossification, i.e. direct ossification on the surface of the terminal phalanx, whereas proximal elongation results from an endochondral growth plate. Amputation through the middle of the terminal phalanx regenerates whereas regenerative failure is observed following amputation to remove the distal 2/3 of the bone. Regeneration is characterized by the formation of a blastema of proliferating cells that appear undifferentiated and express Bmp4. Using chondrogenic and osteogenic markers we show that redifferentiation does not occur by endochondral ossification but by the direct ossification of blastema cells that form the rudiment of the digit tip. Once formed the rudiment elongates by appositional ossification in parallel with unamputated control digits. Regenerated digits are consistently shorter than unamputated control digits. Finally, we present a case study of a child who suffered an amputation injury at a proximal level of the terminal phalanx, but failed to regenerate despite conservative treatment and the presence of the nail organ. These clinical and experimental findings expand on previously published observations and initiate a molecular assessment of a mammalian regeneration model.

Tissue response and Msx1 expression after human fetal digit tip amputation in vitro.

Regeneration of mammalian digit tips is well described; however, associated cellular or molecular events have not been studied in humans. We describe an in vitro human fetal model of response to digit tip amputation, and report expression of the transcription repressor Msx1 in the developing and regrowing human digit tip. Human fetal digits from specimens ranging from 53 to 117 days' estimated gestational age (EGA) were cultured in a defined serum-free medium with supplemented oxygen for time periods from 4 days to 4 weeks. Histology and immunohistochemistry were performed on paired control and tip-amputated digits. Regrowing tissue covered the cut end of the distal phalanx in digits up to 80 days' EGA. Msx1 expression was detected beneath the nail field in control digits to at least 70 days' EGA and at the regrowing tip of 57-day digits at 4 and 7 days post-amputation. Our results show that human fetal digits regrow tissue in vitro in response to tip amputation. This process appears spatially associated with Msx1 expression. Msx1 expression appears increased at the regrowing tip of 57-day digits by 4 days after amputation.

Flexor tendons: anatomy and surgical approaches.

The nature of the original injury is the chief determinant of outcome and is out of the control of the surgeon. Every step thereafter can be influenced by him or her, though, and a thorough knowledge of anatomy and surgical approaches allows for the best possible repair under any set of circumstances.