Mg-Zn-Ca Alloy (ZX00) Screws Are Resorbed at a Mean of 2.5 Years After Medial Malleolar Fracture Fixation: Follow-up of a First-in-humans Application and Insights From a Sheep Model.

BACKGROUND: In the ongoing development of bioresorbable implants, there has been a particular focus on magnesium (Mg)-based alloys. Several Mg alloys have shown promising properties, including a lean, bioresorbable magnesium-zinc-calcium (Mg-Zn-Ca) alloy designated as ZX00. To our knowledge, this is the first clinically tested Mg-based alloy free from rare-earth elements or other elements. Its use in medial malleolar fractures has allowed for bone healing without requiring surgical removal. It is thus of interest to assess the resorption behavior of this novel bioresorbable implant. QUESTIONS/PURPOSES: (1) What is the behavior of implanted Mg-alloy (ZX00) screws in terms of resorption (implant volume, implant surface, and gas volume) and bone response (histologic evaluation) in a sheep model after 13 months and 25 months? (2) What are the radiographic changes and clinical outcomes, including patient-reported outcome measures, at a mean of 2.5 years after Mg-alloy (ZX00) screw fixation in patients with medial malleolar fractures? METHODS: A sheep model was used to assess 18 Mg-alloy (ZX00) different-length screws (29 mm, 24 mm, and 16 mm) implanted in the tibiae and compared with six titanium-alloy screws. Micro-CT was performed at 13 and 25 months to quantify the implant volume, implant surface, and gas volume at the implant sites, as well as histology at both timepoints. Between July 2018 and October 2019, we treated 20 patients with ZX00 screws for medial malleolar fractures in a first-in-humans study. We considered isolated, bimalleolar, or trimalleolar fractures potentially eligible. Thus, 20 patients were eligible for follow-up. However, 5% (one patient) of patients were excluded from the analysis because of an unplanned surgery for a pre-existing osteochondral lesion of the talus performed 17 months after ZX00 implantation. Additionally, another 5% (one patient) of patients were lost before reaching the minimum study follow-up period. Our required minimum follow-up period was 18 months to ensure sufficient time to observe the outcomes of interest. At this timepoint, 10% (two patients) of patients were either missing or lost to follow-up. The follow-up time was a mean of 2.5 ± 0.6 years and a median of 2.4 years (range 18 to 43 months). RESULTS: In this sheep model, after 13 months, the 29-mm screws (initial volume: 198 ± 1 mm3) degraded by 41% (116 ± 6 mm3, mean difference 82 [95% CI 71 to 92]; p < 0.001), and after 25 months by 65% (69 ± 7 mm3, mean difference 130 [95% CI 117 to 142]; p < 0.001). After 13 months, the 24-mm screws (initial volume: 174 ± 0.2 mm3) degraded by 51% (86 ± 21 mm3, mean difference 88 [95% CI 52 to 123]; p = 0.004), and after 25 months by 72% (49 ± 25 mm3, mean difference 125 [95% CI 83 to 167]; p = 0.003). After 13 months, the 16-mm screws (initial volume: 112 ± 5 mm3) degraded by 57% (49 ± 8 mm3, mean difference 63 [95% CI 50 to 76]; p < 0.001), and after 25 months by 61% (45 ± 10 mm3, mean difference 67 [95% CI 52 to 82]; p < 0.001). Histologic evaluation qualitatively showed ongoing resorption with new bone formation closely connected to the resorbing screw without an inflammatory reaction. In patients treated with Mg-alloy screws after a mean of 2.5 years, the implants were radiographically not visible in 17 of 18 patients and the bone had homogenous texture in 15 of 18 patients. No clinical or patient-reported complications were observed. CONCLUSION: In this sheep model, Mg-alloy (ZX00) screws showed a resorption to one-third of the original volume after 25 months, without eliciting adverse immunologic reactions, supporting biocompatibility during this period. Mg-alloy (ZX00) implants were not detectable on radiographs after a mean of 2.5 years, suggesting full resorption, but further studies are needed to assess environmental changes regarding bone quality at the implantation site after implant resorption. CLINICAL RELEVANCE: The study demonstrated successful healing of medial malleolar fractures using bioresorbable Mg-alloy screws without clinical complications or revision surgery, resulting in pain-free ankle function after 2.5 years. Future prospective studies with larger samples and extended follow-up periods are necessary to comprehensively assess the long-term effectiveness and safety of ZX00 screws, including an exploration of limitations when there is altered bone integrity, such as in those with osteoporosis. Additional use of advanced imaging techniques, such as high-resolution CT, can enhance evaluation accuracy.

Does early post-operative exercise influence bone healing kinetics? Preclinical evaluation of non-critical sized femur defect healing.

Physical exercise is a well-known modality for maintaining healthy locomotor mechanism. A detailed preclinical research on physical exercise effect on bone healing kinetics could help to improve the rehabilitation process after fracture treatment and bone remodeling. Our aim was to evaluate the effect of early post-operative exercise effect on bone microstructural changes in a rat model. Twenty Sprague Dawley male rats underwent bi-cortical 1.6 mm hole drilling in both femur diaphysis, after which (n = 10) underwent continuous treadmill training (TR) over two weeks, while the other group of rats (n = 10) was assigned to non-training (NT) control group. New bone formation labeling was performed by subcutaneous fluorochrome injections at day 5, 14 and 31. In vivo micro-computed tomography (µCT) scans were performed once a week during the 6-week post-operative period. Ten animals (five from each group) were euthanized at 3rd week while remaining animals were euthanized at 6th week. Femur samples were extracted and underwent ex vivo µCT and histological evaluation, while serum was used for evaluating alkaline phosphatase (ALP). µCT data demonstrated increased volume and surface of newly formed bone in defect area of TR group. Bone volume/Tissue volume (BV/TV) ratio and number of osteocytes showed an increase in TR group after 3-week period. Fluorochrome distances were increased between day 5 and 14 within the training group. Serum ALP level increased in both groups over 3- and 6-weeks. Post-operative exercise increases the bone healing kinetics and stimulates the new bone formation during and after the training protocol has ended.

The combined effect of zinc and calcium on the biodegradation of ultrahigh-purity magnesium implants.

Magnesium (Mg)-based implants are promising candidates for orthopedic interventions, because of their biocompatibility, good mechanical features, and ability to degrade completely in the body, eliminating the need for an additional removal surgery. In the present study, we synthesized and investigated two Mg-based materials, ultrahigh-purity ZX00 (Mg-Zn-Ca; <0.5 wt% Zn and <0.5 wt% Ca, in wt%; Fe-content <1 ppm) and ultrahigh-purity Mg (XHP-Mg, >99.999 wt% Mg; Fe-content <1 ppm), in vitro and in vivo in juvenile healthy rats to clarify the effect of the alloying elements Zn and Ca on mechanical properties, microstructure, cytocompatibility and degradation rate. Potential differences in bone formation and bone in-growth were also assessed and compared with state-of-the-art non-degradable titanium (Ti)-implanted, sham-operated, and control (non-intervention) groups, using micro-computed tomography, histology and scanning electron microscopy. At 6 and 24 weeks after implantation, serum alkaline phosphatase (ALP), calcium (Ca), and Mg level were measured and bone marrow stromal cells (BMSCs) were isolated for real-time PCR analysis. Results show that ZX00 implants have smaller grain size and superior mechanical properties than XHP-Mg, and that both reveal good biocompatibility in cytocompatibilty tests. ZX00 homogenously degraded with an increased gas accumulation 12 and 24 weeks after implantation, whereas XHP-Mg exhibited higher gas accumulation already at 2 weeks. Serum ALP, Ca, and Mg levels were comparable among all groups and both Mg-based implants led to similar relative expression levels of Alp, Runx2, and Bmp-2 genes at weeks 6 and 24. Histologically, Mg-based implants are superior for new bone tissue formation and bone in-growth compared to Ti implants. Furthermore, by tracking the sequence of multicolor fluorochrome labels, we observed higher mineral apposition rate at week 2 in both Mg-based implants compared to the control groups. Our findings suggest that (i) ZX00 and XHP-Mg support bone formation and remodeling, (ii) both Mg-based implants are superior to Ti implants in terms of new bone tissue formation and osseointegration, and (iii) ZX00 is more favorable due to its lower degradation rate and moderate gas accumulation.

Immunological reaction to magnesium-based implants for orthopedic applications. What do we know so far? A systematic review on in vivo studies.

Magnesium-based implants (Mg) became an attractive candidate in orthopedic surgery due to their valuable properties, such as osteoconductivity, biodegradability, elasticity and mechanical strength. However, previous studies on biodegradable and non-biodegradable metal implants showed that these materials are not inert when placed in vivo as they interact with host defensive mechanisms. The aim of this study was to systematically review available in vivo studies with Mg-based implants that investigated immunological reactions to these implants. The following questions were raised: Do different types of Mg-based implants in terms of shape, size and alloying system cause different extent of immune response? and; Are there missing links to properly understand immunological reactions upon implantation and degradation of Mg-based implants? The database used for the literature research was PubMed (U.S. National Library of Medicine) and it was undertaken in the end of 2021. The inclusion criteria comprised (i) in vivo studies with bony implantation of Mg-based implants and (ii) analysis of the presence of local immune cells or systemic inflammatory parameters. We further excluded any studies involving coated Mg-implants, in vitro studies, and studies in which the implants had no bone contact. The systematic search process was conducted according to PRISMA guidelines. Initially, the search yielded 225 original articles. After reading each article, and based on the inclusion and exclusion criteria, 16 articles were included in the systematic review. In the available studies, Mg-based implants were not found to cause any severe inflammatory reaction, and only a mild to moderate inflammatory potential was attributed to the material. The timeline of foreign body giant cell formation showed to be different between the reviewed studies. The variety of degradation kinetics of different tested implants and discrepancies in studies regarding the time points of immunological investigations impair the conclusion of immunological reactions. This may be induced by different physical properties of an implant such as size, shape and alloying system. Further research is essential to elucidate the underlying mechanisms by which implant degradation affects the immune system. Also, better understanding will facilitate the decision of patients whether to undergo surgery with new device implantation.

CLINICAL EFFECTS OF HYPERBARIC LIDOCAINE AND BUPIVACAINE IN SPINAL ANESTHESIA - OUR EXPERIENCE.

Introduction: Various side effects and complications in the perioperative period can occur with the use of hyperbaric lidocaine and bupivacaine. Goal: Comparative presentation of the occurrence of side effects and complications of hyperbaric lidocaine and bupivacaine during spinal anesthesia in our patients. Methods: The study was retrospective and included 178 patients of both sexes. Patients were divided into two groups. In Group I (n-98) hyperbaric lidocaine 5% was used for spinal block. Group II (n-80) was divided into 2 subgroups, A- where hyperbaric Markain 0.5% was used (n-51), and B (n-29) where hyperbaric Sensorkain 0.75% was used. In the study, we analyzed gender, age, block onset, and complications. Results: There were 98 patients in Group I, 79 males and 19 females. There were 80 patients in Group II, 69 males and 11 females. The mean age of patients in Group I was 44.96 and in Group II 48.16 years. There was no statistically significant difference in the age of patients in both groups p> 0.05 (p = 0.2321). The occurrence of spinal block occurred significantly faster in Group I compared to group II (p <0.0001), and in subgroup B faster than in subgroup A (p <0.005). The clinical occurrence of complications and side effects during spinal anesthesia is somewhat more common in spinal block with 5% lidocaine. Conclusion: The compared incidence of adverse perioperative clinical effects and complications after administration of hyperbaric lidocaine and bupivacaine in spinal anesthesia was not statistically significant.

The preemptive effect of tramadol and metamizole on the intensity of postoperative pain.

Aim To demonstrate the analgesic effect of preemptively administered tramadol and metamizole on the postoperative pain severity, after an elective operative hysterectomy with adnexectomy. Methods There were three groups with 30 patients in each group. Patients included in the study were between 45 to 67 years old. They were all in the ASA group II. Randomization was performed in random order according to the regular elective operating program. Patients in Group I received i. m. tramadol 1mg/kg, and in Group II 30mg/kg of metamizole, five minutes before anaesthesia induction. Patients did not receive preemptive analgesia in Group III (control). All patients underwent the same induction anaesthesiology procedure with propofol, fentanyl, tracrium, supplemented with O2, N2O, and sevoflurane at an appropriate dose until MAC 1 was reached. Surgeries lasted for 80-120 minutes. Every patient performed a resting pain assessment 30 minutes after an extubation by Numerical Pain Scale (NPS). Results We found out that tramadol had a better effect in preemptive analgesia and that the average pain score for Group I was 6.10 (p=0.043). In Group II, it was 7.93 (p=0.022). There is significant difference in pain intensity between patients in the control group, (pain intensity was 9.16), and those who received tramadol and metamizole. There was no significant difference in the intensity of pain when using these two analgesics (p=0.733). Conclusion The effect of preemptively administered tramadol prior to the introduction of general anaesthesia in postoperative pain is significantly more favourable than the effect of metamizole.

COMPARISON OF PLEXUS BRACHIAL BLOCKADE EFFECT BY SUPRACLAVICULAR AND AXILLARY APPROACH - OUR EXPERIENCE.

INTRODUCTION: Brachialis plexus block is a frequently used method of regional anesthesia that can be performed in several ways and locations. It has been successfully performed to provide good anesthesia and analgesia lasting several hours for operative procedures on hands. It can be performed by paresthesia technique or by ultrasound that has almost pushed out the old conventional technique since it allows the visualization of the blockade performance. TARGET: In the paper we use our sample to try to determine which of the two locations of the blockageis more favorable for the patient, and which one gives a higher percentage of success or a better sensory blockade. METHOD: This is a retrospective study and includes 40 patients of both sexes that were operated on at the Clinic for Traumatology and the Clinic for Plastic Surgery of the University Clinical Center in Sarajevo in the period from 30 August 1993 to 30 August 1994. Patients were divided into two groups. Group I were patients who had an axillary approach to plexus brachialis (n-21) ASA I-II. Group II were patients who had supraclavicular access to plexus brachialis (n-19) ASA I-II. All patients received 0.5 ml / kg Bupivacaine 0.5%. In the study, we analyzed sex, age, duration of blockade and complications. Analgesia and motor block were evaluated 20 minutes after the local anesthetic injection. The complete block is defined as analgesia in all dermatomes (C5-Th1) 20 minutes after injection. THE RESULTS: Group I had 20 male and 1 female patients while group II had 17 male and 2 female patients. The supraclavicular block enabled complete blockade in 18 patients (95.23%), and the axillary approach had a successful blockade in 17 patients (80.95%). In both groups the corresponding motor block was similar. The start of the engine block was similar in both groups. There were no significant complications in either group. CONCLUSION: Regarding clinical efficacy, both brachial plexus blocking approaches provided a good motor block, anesthesia and analgesia for the forearm or hand surgery. Supraclavicular approach proved to be more favorable.