MaCalus V. Hogan

Adipose-Derived Mesenchymal Stem Cells Treated with Growth Differentiation Factor-5 Express Tendon-Specific Markers

OBJECTIVES Adipose-derived mesenchymal stem cells (ADMSCs) are a unique population of stem cells with therapeutic potential in the treatment of connective tissue injuries. Growth differentiation factor-5 (GDF)-5 is known to play a role in tendon repair and maintenance. The aim of this study was to investigate the effects of GDF-5 on proliferation and tendonogenic gene expression of rat ADMSCs. METHODS ADMSCs were treated in culture with different concentrations of GDF-5 (0-1000 ng/mL) for 12 days. Biochemical, temporal, and concentration kinetic studies were done. Extracellular matrix (ECM) synthesis, tendonogenic differentiation, and matrix remodeling gene and protein expression were analyzed. RESULTS GDF-5 led to increased ADMSC proliferation in a dose- and time-dependent manner. ADMSCs demonstrated enhanced ECM (collagen type I, decorin, and aggrecan) and tendonogenic marker (scleraxis, tenomodulin, and tenascin-C) gene expression with 100 ng/mL of GDF-5 (p < 0.05). ECM and tendon-specific markers showed time-dependent increases at various time points (p < 0.05), although decorin decreased at day 9 (p < 0.05). GDF-5 did alter expression of matrix remodeling genes, with no specific trends observed. Western blot analysis confirmed dose- and time-dependent increases in protein expression of tenomodulin, tenascin-C, Smad-8, and matrix metalloproteinase-13. CONCLUSION In vitro GDF-5 treatment can induce cellular events leading to the tendonogenic differentiation of ADMSCs. The use of combined GDF-5 and ADMSCs tissue-engineered therapies may have a role in the future of tendon repair.

Peripheral nerve repair and reconstruction.

When possible, direct repair remains the current standard of care for the repair of peripheral nerve lacerations. In large nerve gaps, in which direct repair is not possible, grafting remains the most viable option. Nerve scaffolds include autologous conduits, artificial nonbioabsorbable conduits, and bioabsorbable conduits and are options for repair of digital nerve gaps that are <3 cm in length. Experimental studies suggest that the use of allografts may be an option for repairing larger sensory nerve gaps without associated donor-site morbidity.

Recent Patents on Electrospun Biomedical Nanostructures: An Overview

Nanostructures in the form of tubes, wires, crystals, rods, spheres, and fibers have been fabricated and assembled into various macrostructures for a variety of high technology applications. Nanofeatures impart several amazing properties to these macrostructures including high surface area, surface functionality, and superior mechanical, optical, electrical, and magnetic properties over the parent bulk material. Polymeric nanofibers in the form of nonwoven cloth, membrane, braids and tubes are extensively used for daily needs, and in addition used as filters, protective clothing, and for a variety of industrial and biomedical applications. Electrospinning or electrostatic spinning has emerged as a very popular technique to fabricate polymeric nanofiber matrices. More than 100 different polymers of natural, synthetic origin, their blends and composites have been electrospun into different three dimensional (3-D) macrostructures. Electrospinning provides opportunities to manipulate and control surface area, fiber diameter, porosity and pore size of nanofiber matrices. These nanofiber matrices closely mimic the structure of extracellular matrix (ECM) and influence cellular activities both in vitro and in vivo. Nanofiber macrostructures have been used as a vehicle to deliver therapeutic agents, as scaffolds for engineering various tissues and also serve as an integrated part of biomedical implants. Present review will cover some of the recent important patents that use electrospun nanofiber matrices for various biomedical applications.

Nerve conduits for nerve repair or reconstruction.

Advances in treating peripheral nerve lesions have resulted from research in nerve regeneration and the use biomaterials as well as synthetic materials. When direct tensionless repair of peripheral nerve lesions is not possible, nerve conduits may be used to bridge digital sensory nerve gaps of ≤3 cm. Nerve autograft is the benchmark for larger, longer, mixed, or motor nerve defects. Biologic, autogenous conduits-typically veins or, rarely, arteries-have demonstrated their utility in nerve gaps <3 cm in length. Three types of bioabsorbable conduit have been approved by the US Food and Drug Administration, constructed of collagen, polyglycolic acid, or caprolactone. Caprolactone conduits have been found to be equivalent in results to autograft. Collagen conduits are next best, and polyglycolic acid conduits are functionally inferior. Further research and prospective, multicenter, large-scale trials are needed to help establish the role of synthetic, bioabsorbable conduits in peripheral nerve reconstruction.

Critical analysis of the evidence for current technologies in bone-healing and repair.

Substances that enhance fracture-healing and bone regeneration have valuable clinical application and merit future research. Advances in these technologies will enhance our ability to heal fractures in a more effective and expedient manner. This review provides a brief description of the different techniques and technologies and their respective clinical utility. This paper also reviews the available literature on gene therapy, tissue engineering, growth factors, osteoconductive agents, and physical forces and assesses the evidence regarding the current status of these techniques of healing and regenerating bone. Only twenty-seven articles met our guidelines for studies containing Level-I evidence. We were able to determine that atrophic nonunions and pseudarthrosis led to poorer outcomes, and the results were uniformly poor irrespective of the technique used. Although the literature contains a large number of studies on the effects of different agents and modalities on bone repair and healing, it still is not clear how these agents work or in what circumstances they should be used. Many of the treatment modalities of interest are still at an experimental stage, so good evidence to support clinical practice is lacking. Additional multicenter, prospective randomized studies are needed to define the indications, specifications, dosage, limitations, and contraindications in the treatment of nonunions. Studies are also needed to address the full clinical feasibility of the role of each modality in fracture-healing and repair.

Tissue engineering solutions for tendon repair.

Abstract Tendon injuries range from acute traumatic ruptures and lacerations to chronic overuse injuries, such as tendinosis. Even with improved nonsurgical, surgical, and rehabilitation techniques, outcomes following tendon repair are inconsistent. Primary repair remains the standard of care. However, repaired tendon tissue rarely achieves functionality equal to that of the preinjured state. Poor results have been linked to alterations in cellular organization within the tendon that occur at the time of injury and throughout the early stages of healing. Enhanced understanding of the biology of tendon healing is needed to improve management and outcomes. The use of growth factors and mesenchymal stem cells and the development of biocompatible scaffolds could result in enhanced tendon healing and regeneration. Recent advances in tendon bioengineering may lead to improved management following tendon injury.

Arthroscopic Bone Marrow Stimulation and Concentrated Bone Marrow Aspirate for Osteochondral Lesions of the Talus: A Case-Control Study of Functional and Magnetic Resonance Observation of Cartilage Repair Tissue Outcomes.

PURPOSE This study compares retrospective functional and magnetic resonance imaging (MRI) outcomes after arthroscopic bone marrow stimulation (BMS) with and without concentrated bone marrow aspirate (cBMA) as a biological adjunct to the surgical treatment of osteochondral lesions (OCLs) of the talus. METHODS Twenty-two patients who underwent arthroscopic BMS with cBMA (cBMA/BMS group) for an osteochondral lesion (OCL) of the talus and 12 patients who underwent arthroscopic BMS (BMS alone) for an OCL of the talus were retrospectively reviewed. The Foot and Ankle Outcome Score (FAOS) pain subscale and Short Form 12 general health questionnaire physical component summary score (SF-12 PCS) provided patient-reported outcome scores pre- and postoperatively. MRI scans were assessed postoperatively using the magnetic resonance observation of cartilage repair tissue (MOCART) score. All patients had postoperative MRI performed at the 2-year postoperative visit, and quantitative T2 mapping relaxation time values were assessed in a subset of the cBMA/BMS group. RESULTS The mean FAOS and SF-12 PCS scores improved significantly pre- to post-operatively (P < .01) at a mean follow-up of 48.3 months (range, 34 to 82 months) for the cBMA/BMS group and 77.3 months (range, 46 to 100 months) for the BMS-alone group. The MOCART score in the cBMA/BMS group was significantly higher than that in the BMS-alone group (P = .023). Superficial and deep T2 relaxation values in cBMA/BMS patients were higher in repair tissue compared with measurements in adjacent native articular cartilage (P = .030 and P < .001, respectively). CONCLUSIONS BMS is an effective treatment strategy for treatment of OCLs of the talus and results in good medium-term functional outcomes. Arthroscopic BMS with cBMA also results in similar functional outcomes and improved border repair tissue integration, with less evidence of fissuring and fibrillation on MRI.

The Role of Stem Cells and Tissue Engineering in Orthopaedic Sports Medicine: Current Evidence and Future Directions

The use of stem cell therapies for the treatment of orthopaedic injuries continues to advance. The purpose of this review was to provide an update of the current role and future directions of stem cell strategies in sports medicine. The application of cell-based treatments in the sports medicine arena has expanded in recent years. Promising preclinical results have led to translation of these novel therapies into the clinical setting. Early well-designed comparative clinical studies have also shown positive outcomes. Despite significant advances in this arena, there remains a need for additional high-powered and well-designed clinical trials to confirm the safety and efficacy of treatment.

Investigating the Relationship Between Ankle Arthrodesis and Adjacent-Joint Arthritis in the Hindfoot. A Systematic Review.

BACKGROUND Ankle arthrodesis traditionally has been regarded as the treatment of choice for many patients with end-stage ankle arthritis. However, a major reported risk of ankle arthrodesis is adjacent-joint degeneration. There are conflicting views in the literature as to the causative link between ankle arthrodesis and progression to adjacent-joint arthritis. Recent studies have challenged the causative link between arthrodesis and adjacent-joint arthritis, purporting that preexisting adjacent-joint arthritis is present in many patients. The aim of the present study was to systematically review the available literature to determine if there is sufficient evidence to support either hypothesis. METHODS A literature search of the EMBASE and PubMed/MEDLINE databases (1974 to present) was performed. A total of twenty-four studies were included for review. The studies were reviewed, and the relevant information was extracted, including research methodology, postoperative outcomes in the adjacent joints of the foot, and whether pre-arthrodesis radiographs and medical records were available for analysis. RESULTS The twenty-four manuscripts included eighteen clinical studies, five biomechanical studies, and one gait-analysis study. The majority of biomechanical studies showed altered biomechanics in the fused ankle; however, there was no clear consensus as to whether these findings were causes of adjacent-joint arthritis. In studies assessing clinical outcomes, the reported prevalence of subtalar joint arthritis ranged from 24% to 100% and the prevalence of talonavicular and calcaneocuboid arthritis ranged from 18% to 77%. Correlation between imaging findings of arthritis in adjacent joints and patient symptoms was not established in a number of the clinical studies reviewed. CONCLUSIONS There is no true consensus in the literature as to the effects of ankle arthrodesis on biomechanics or whether ankle arthrodesis leads to adjacent-joint arthritis. Similarly, a correlation between postoperative imaging findings and clinical presentation in this cohort of patients has not been conclusively demonstrated.

The Indications and Use of Bone Morphogenetic Proteins in Foot, Ankle, and Tibia Surgery

Tissue engineering is an area of rapid growth. Tissue engineering in orthopedic surgery involves the use of growth factors, mesenchymal stem cells, and scaffolds, individually or in combination, toward the growth and restoration of various musculoskeletal tissues, such as ligaments, tendons, muscles, nerves, and bone. These advances are constantly evolving in foot and ankle surgery as well. Bone morphogenetic proteins (BMPs) have played an integral role in the advancement of tissue engineering strategies across multiple orthopedic subspecialities and have proved to play a role in the development of bone and musculoskeletal tissues. BMPs have recently been applied in several areas of foot and ankle surgery, including acute fracture augmentation, nonunions, and arthrodesis, with promising results. This article reviews the key aspects of clinical translation of strategies in tissue engineering as well as current applications and results of BMP use in tibia, foot, and ankle surgery. Future applications of BMP and novel materials in foot and ankle surgery are also reviewed.