Use of stem cells and growth factors in rotator cuff tendon repair.

The management of rotator cuff tears continues to prove challenging for orthopaedic surgeons. Such tears affect most age groups and can lead to significant morbidity in patients. The aetiology of these tears is likely to be multifactorial; however, an understanding of the mechanisms involved is still under review. Despite advancements in surgical operative techniques and the materials used, post-operative recurrence rates after surgical repair remain high. A growing area of research surrounds biological adjuncts used to improve the healing potential of the repaired tissues. This review of recent publications focuses on the strengths and limitations of using stem cells and growth factors in rotator cuff repair.

Optimization of a Labeling and Kit Preparation Method for Ga-68 Labeled DOTATATE, Using Cation Exchange Resin Purified Ga-68 Eluates Obtained from a Tin Dioxide 68Ge/68Ga Generator.

PURPOSE: The aim of this study was to optimize a radiolabeling method using cationic processed Ga-68 eluates from a SnO2-based 68Ge/68Ga generator, followed by the development of DOTA-Tyr3-Thre8-octreotide (DOTATATE) kits. PROCEDURES: Diluted generator eluates were adsorbed on a SCX resin and desorbed with acidified 5 M NaCl solution. Optimized labeling conditions were determined by variation of pH, using 35 µg DOTATATE and sodium acetate buffer. DOTATATE kits were developed based on optimized radiolabeling conditions, were labeled, and evaluated. RESULTS: Optimized labeling conditions resulted in a radiolabeling efficiency of around 99 % and radiochemical yield of almost 85 %. Different kit preparation methods did not significantly influence the radiolabeling results. Kits were found to be stable over 3 months. CONCLUSION: A labeling method using SCX-processed Ga-68 eluates was optimized. DOTATATE kits specifically for these SCX-processed Ga-68 eluates were successfully formulated. A post-labeling Sep-Pak C18 purification should be optional.

Development and Evaluation of User-Friendly Single Vial DOTA-Peptide Kit Formulations, Specifically Designed for Radiolabelling with 68Ga from a Tin Dioxide 68Ge/68Ga Generator.

PURPOSE: This study was aimed to develop single vial 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide kits to be used with fractionated eluates from a SnO2-based 68Ge/68Ga generator. PROCEDURES: Kits were formulated with 35 µg DOTA-Tyr3-Thre8-octreotide, DOTA-[Tyr3]-octreotide and DOTA-[NaI3]-octreotide (DOTATATE, DOTATOC and DOTANOC) and sodium acetate powder, vacuum-dried and stored at -20 °C for up to 12 months. Labelling of the kits was carried out with 2 ml 68Ga eluate. Comparative labelling was carried out using aqueous DOTA-peptide stock solutions kept frozen at -20 °C for up to 12 months. RESULTS: The quality of the kits was found to be suitable over a 1-year storage period (pH, sterility, endotoxin content, radiolabelling efficiency and radiochemical yields of 68Ga-labelled DOTA-peptides). Radiochemical yields ranged from 73 to 83 %, while those obtained from stock solutions from 64 to 79 %. No significant decline in kit labelling yields was observed over a 12-month storage period. CONCLUSION: The single vial kit formulations met the quality release specifications for human administration and appear to be highly advantageous over using peptide stock solutions in terms of stability and user-friendliness.

Evaluation of a Flexible NOTA-RGD Kit Solution Using Gallium-68 from Different 68Ge/68Ga-Generators: Pharmacokinetics and Biodistribution in Nonhuman Primates and Demonstration of Solitary Pulmonary Nodule Imaging in Humans.

PURPOSE: Radiopharmaceuticals containing the motive tripeptide arginyl-glycyl-asparatic acid (RGD) are known to target ανß3 integrins during tumor angiogenesis. A more generic kit radiolabeling procedure accommodating Ga-68 from different generators was developed for NOTA-RGD and evaluated for its versatile use and safety in subsequent in vivo applications. The [68Ga]NOTA-RGD kit was further verified for its expected biodistribution and pharmacokinetics in nonhuman primates and its clinical sensitivity to detect solitary pulmonary nodules (SPN) in cancer patients. PROCEDURES: Single vial kits containing 28-56 nmol of NOTA-cyclo-Arg-Gly-Asp-d-Tyr-Lys (NOTA-RGD) and sodium acetate trihydrate buffer were formulated. Versatility of the NOTA-RGD radiolabeling performance and adaption to a TiO2- and a SnO2-based generator type, characterization and long-term storage stability of the kits were carried out. The blood clearance and urine recovery kinetics as well as the image-guided biodistribution of [68Ga]NOTA-RGD was studied in a vervet monkey model. [68Ga]NOTA-RGD kits were further tested clinically to target solitary pulmonary nodules. RESULTS: The kits could be successfully formulated warranting integrity over 3-4 months with a good [68Ga]NOTA-RGD radiolabeling performance (radiochemical purity >95 %, decay corrected yield 76-94 %, specific activity of 8.8-37.9 GBq/µmol) The kits met all quality requirements to be further tested in vivo. [68Ga]NOTA-RGD cleared rapidly from blood and was majorly excreted via the renal route. The liver, spleen, heart and intestines showed initial uptake with steadily declining tissue activity concentration over time. In addition, the [68Ga]NOTA-RGD kit allowed for delineation of SPN from non-malignant lung tissue in humans. CONCLUSIONS: A more versatile radiolabeling procedure using kit-formulated NOTA-RGD and different generator types was achieved. The uncompromised in vivo behavior and efficient targeting of SPN warrants further investigations on the clinical relevance of [68Ga]NOTA-RGD derivatives to implement initial guidelines and management of patients, with regard to integrin targeted imaging.

Scaled-up radiolabelling of DOTATATE with 68Ga eluted from a SnO2-based 68Ge/68Ga generator.

A scaled-up radiolabelling and improved post-labelling purification procedure for [(68)Ga]DOTATATE is reported, using a more than 1 year old SnO(2)-based 1850MBq (68)Ge/(68)Ga generator (initially double-loaded with 3700MBq (68)Ge) as a source of ionic (68)Ga. The elution method of choice comprised elution with 0.6M HCl in a single 4mL fraction, containing up to 95% of the total eluted (68)Ga activity. The unpurified fraction was directly used for labelling after pH adjustment with 2.5M sodium acetate. Labelling efficiencies were determined at 90-95°C at various reaction times and reaction volumes of up to 5.7mL, using either 30µg or 50µg DOTATATE. Only the latter amount resulted in consistently high labelling efficiency in excess of 95%. Post-labelling purification, carried out on Sep-Pak C18, showed that 50% ethanol in saline was a superior desorption eluant than 100% ethanol. The highest and most consistent decay-corrected radiochemical yields (89%) were obtained using 50µg DOTATATE and a 20min reaction time.

Use of a partial humeral head resurfacing system for management of an osseous mechanical block to glenohumeral joint range of movement secondary to proximal humeral fracture malunion.

Malunion of proximal humeral fractures can lead to a severely impaired shoulder function. Loss of motion is often the main issue in patients and can be secondary to osseous, soft-tissue as well as neurological damage to the shoulder. Malunion of the articular surface of the humeral head can lead to pain, chronic degenerative changes secondary to joint incongruity and mechanical block to the range of movement. A 46-year-old otherwise healthy male chef presented with malunion and collapse of his previous plate fixation for a four-part proximal humerus fracture. We describe the first documented case of the use of a focal resurfacing system for dealing with such an osseous mechanical block in the presence of an otherwise preserved articular surface in a high-demand patient. HemiCAP can be successfully used in proximal humeral fracture malunion where there is a localized cartilage defect, allowing restoration of joint congruity while preserving the bone stock.

Radiosynthesis and evaluation of two novel 123I-labeled 2-methyl-4-nitroimidazole derivatives as potential infection imaging agents.

INTRODUCTION: The inflammation- and infection-seeking properties of (131)I-labeled ornidazole, a 5-nitroimidazole derivative, have recently been reported. Whole-body images in rabbits showed a more rapid uptake in inflamed areas compared to (67)Ga. In the present study, two novel (123)I-labeled 2-methyl-4-nitroimidazole derivatives were synthesized and their infection-seeking properties compared with those of (67)Ga and (123)I-labeled ornidazole. METHODS: Radiolabeling was carried out by means of iodide-for-tosylate, triflate or halogen exchange. Various methods were utilized in order to synthesize the labeling precursors for the (123)I-labeled novel compounds. Serum stability studies on all of the (123)I-labeled tracers were followed by gamma camera imaging studies on rabbits artificially infected with Escherichia coli bacteria. RESULTS AND CONCLUSIONS: The (123)I-labeled tracers were obtained in moderate to good radiochemical yields (34-80%) and acceptable radiochemical purities (93-99%). In contrast to (123)I-labeled ornidazole, 1-[(1-hydroxy-3-[(123)I]iodoprop-2-yloxy)methyl]-2-methyl-4-nitroimidazole (2) and 1-[(1-[(123)I]iodoprop-2-yloxy)methyl]-2-methyl-4-nitroimidazole (3) showed high serum stability. Compared to noninfected controls, all of the (123)I-labeled tracers showed increased uptake at the area of induced infection after 6 and 24 h, but the uptake was significantly lower than in the case of (67)Ga over the same period. Tracer 3 showed a slightly superior uptake after 6 h than the other (123)I-labeled tracers over the same period. The advantage of the initially slightly faster rate at which nitroimidazole tracers appear to accumulate in the infection area in comparison to (67)Ga might not outweigh the advantage of the eventual higher target to nontarget ratio displayed by (67)Ga.