Fig. 39.1
Aqua spec analysis of 11 donors after GOLDIC® incubation: blue, T0; green, T24 GOLDIC; red, T24 control
Based on Aquaspec analysis, the GOLDIC® procedure leads to a significant change of protein quantities and overall composition and highlights individual differences between the different blood samples/patients.
39.4 Protein Analyses of GOLDIC®-Treated Human Serum
Using Elisa and Bioplex assays, protein levels were measured of several important cytokines/chemokines before and 24 h after treatment with the GOLDIC® procedure.
The major effect of the GOLDIC process is indicated by the significant increase of the gelsolin concentration in human serum. Gelsolin is a highly conserved, multifunctional actin-binding protein with an extracellular isoform, plasma gelsolin, for which there is not yet a clearly defined function. The secreted form of gelsolin has been implicated in a number of processes such as the extracellular actin scavenging system and the presentation of lysophosphatidic acid and other inflammatory mediators to their receptors. Additionally, gelsolin functions as a substrate for extracellular matrix-mediating enzymes (Wen et al. 1996; Spinardi and Witke 2007; Li et al. 2012) (Fig. 39.2).
Fig. 39.2
Protein quantification in GOLDIC® serum
Upon GOLDIC® treatment, the highest increase could be found in the following proteins, p-Gelsolin and granulocyte colony-stimulating factor (G-CSF); the following proteins were upregulated also: IL-8, macrophage chemotactic protein (MCP-3), stromal-derived protein (SDF-alpha), tumor necrosis factor-alpha (TNF-alpha), leukemia inhibitory factor (LIF), IL-10, macrophage inflammatory protein (MIP-1alpha), and MIP-1ß. Macrophage colony-stimulating factor (M-CSF), IL-15, IL-17, granulocyte-macrophage colony-stimulating factor (GM-CFS), hepatocyte growth factor (HGF), IL-2Ra, IL-12p40, chemokine (C-C motif) ligand 11 (Eotaxin/CCL11), fibroblast growth factor-basic (bFGF), and interferon-gamma (IFN-g)
GOLDIC treatment failed to induce differential expression of IL-2, IL-3, IL-4, IL-5, IL-7, IL-9, IL-13, IL-18, C-C chemokine receptor type 10 (CCR10), and interferon alpha 2 (IFN-a2).
39.5 First Clinical Results After GOLDIC® Treatment
39.5.1 Clinical Studies in Horses
The aim of the first clinical study was to determine the effectiveness of GOLDIC injections in horses with different lameness-associated diseases. In a case series study, 36 horses (37 cases) with the clinical sign of lameness were included in this study. The causes for lameness was chondromalacia (n = 19) or soft tissue disorders (n = 18). The horses were treated by four injections of gold-induced, autologous-conditioned serum. The conditioning process included the incubation of the autologous serum with solid gold particles over 24 hours (GOLDIC procedure). Twenty-eight subjects had previously undergone therapeutic interventions, whereas nine had not. Horses were assessed for lameness using the AAEP (American Association of Equine Practitioners) grading scale (0 = no lameness, 5 = severe lameness). Swelling and/or effusion were evaluated in an equal scale between 0 and 5 (0 = no swelling/effusion, 5 = severe swelling/effusion). Scores were collected at pretreatment, and after 1, 2, and 3 weeks, and 3 and 6 months posttreatment. AAEP grading scale score was defined as the primary parameter. A P-value of less than 0.05 was considered statistically significant. In all 37 cases, a significant reduction of lameness, effusion (joint group), and swelling (soft tissue disorders group) within 3 weeks after treatment (p < 0.05) was found. Up to 3 and 6 months after treatment, all horses were free of symptoms. There were no major side effects noted throughout the study (Schneider and Veith 2013).
In a prospective randomized controlled, two-center clinical trial, 30 horses with arthrogenic lameness were enrolled in this study. The horses were treated by four injections of gold-induced, autologous-conditioned serum GOLDIC® (group B, n = 16) or by a single injection of corticosteroid and hyaluronic acid (group A = 14). Lameness was assessed using the AAEP grading system before and 3, 6, 12, and 36 months after treatment. The AAEP grade was the primary endpoint. Differences were considered significant at p < 0.05. Secondary endpoints were the results of the flexion test, degree of joint-effusion, radiographic findings, the ability to return to original performance level, and adverse effects. The GOLDIC®-treated horses showed significantly lower lameness grades at all follow-up examinations compared with the value before treatment (p < 0.01). In horses of group A (control HA + steroid), there was no significant decrease in lameness grade during the follow-up period. Horses of group B had significantly lower lameness grades than horses of group A at all follow-up examinations. Severe adverse events did not occur in either group.
The authors concluded that the treatment of arthrogenic lameness in horses using the gold-induced, autologous-conditioned serum (GOLDIC®) method is superior to the conventional treatment with corticosteroids and hyaluronic acid (Widmer et al. 2017).
39.5.2 Clinical Studies in Humans
In a prospective case series study, patients with chronic Achilles tendinopathy were treated with GOLDIC®. All patients received four peritendinous Achilles injections. Pain score ((VAS) visual analog scale) was evaluated at 4, 12, 24, and 52 months follow-up. MRI follow-up could be performed in five patients before and after 1 year. Adverse events were documented using MedDRA version 12.1.
39.5.2.1 Material and Methods
Nineteen patients (10 male, 9 female) were included in this study. The mean age was 44.5 years (range, 32–80). In 12 cases, the right side was affected and in 7 cases, the left side, respectively.
39.5.2.2 Statistical Analysis
Statistical analysis (Sigma Stat 3.5) was performed by an independent statistician. As normality test failed, data were analyzed by Dunn method, reporting p values with a level of >0.05 indicating significance. Data are expressed as medians and interquartile ranges.
39.5.2.3 Results
After a single four injection GOLDIC® series, the median baseline level was at 6.84 points in the VAS and dropped after 4 months down to 4.16. After 12 months, we found a further improvement in the VAS score down to 2.63. After 2 and 5 years, the VAS score further improved to 1.47 (24 months) and 1.17 (52 months), respectively. In all patient groups, a statistically significant improvement could be demonstrated at all time points compared to baseline (Figs. 39.3).
Fig. 39.3
Demonstration of the VAS score after GOLDIC® treatment. A statistically significant improvement (p < 0.05) compared to baseline could be demonstrated in all patient groups at all time points
All MRIs showed fatty degeneration on the side of the tendinopathy with various sizes. One year after the treatment, all patients showed a complete regeneration of the tendon tissue. This regeneration capacity was not size or age dependent. No severe side effects could be detected (Figs. 39.4 and 39.5).
Fig. 39.4
MRI documentation of a 43-year-old female patient with chronic tendinosis of the Achilles tendon before and 1 year after GOLDIC® treatment. The necrotic tissue inside the tendon was replaced completely by original tendon tissue
Fig. 39.5
MRI documentation of an 80-year-old male patient with chronic tendinosis and a fatty degeneration of the whole middle part of the Achilles tendon before and 1 year after GOLDIC® treatment
These results indicate that the treatment with GOLDIC® injections is safe and has the potential to reduce pain and increase quality of live in patients suffering under chronic Achilles tendinopathy. An impressive regenerative capacity could be demonstrated using MRI even in old patients
39.6 Discussion
While over the last two decades there has been considerable advances in the treatment of tendon disorders, new developments using cell-based and cell-free approaches are under debate. The use of these potential regenerative-acting procedures is still not fully understood, and the results are not consistent. One major problem is the inconsistency of the preparation and processing methods in the cell-based procedures like PRP. This has translated to great variability in clinical outcome of PRPs demonstrated in the literature (Gholami et al. 2016; Mlynarek et al. 2016; Zhou and Wang 2016; Filardo et al. 2016).
Currently the use of mesenchymal stromal cells (MSC) provides an exceptional alternative to conventional methods of tendinopathy treatment. Based on their proliferative potential and immunosuppressive properties, MSC are increasingly used in veterinarian and human medicine; however, the perfect conditions for an effective induction of tendon healing has not been found (Prockop 1997; Tetta et al. 2012; Huang et al. 2013).
The use of growth factors such as HGF, rhPDGF-BB, IL-6, and TGF-β in Achilles tendon repair has shown promising results (Andersen et al. 2011; Aspenberg 2007; Cui et al. 2011; Hou et al. 2009; Kashiwagi et al. 2004; Kessler et al. 2014; Kim et al. 2007; Shah et al. 2013). Bone morphogenetic proteins such as BMP-12, BMP-2, BMP-7, and BMP-14 have also shown positive results for the biological augmentation of Achilles tendon repair (Bolt et al. 2007; Dines et al. 2007; Jelinsky et al. 2011; Keller et al. 2011; Majewski et al. 2008; Rickert et al. 2005). The further investigation of these techniques in a clinical setting is warranted. Another area of great interest is the use of various scaffold material in augmentation of Achilles rupture and repair; however, these materials alone are not enough to achieve a sufficient tendon healing. Scaffolds in combination with biologic material may prove useful in order to optimize the benefits (Adams et al. 2014; Barber et al. 2008; Chen et al. 2010; Cummings et al. 2012; Farnebo et al. 2014; Gilbert et al. 2007; Lee 2007; Lee 2008; Lohan et al. 2013; Majewski et al. 2012; Ning et al. 2012; Nirmalanandhan et al. 2008; Pietschmann et al. 2013; Tang et al. 2014; Webb et al. 2013; Wisbeck et al. 2012; Yao et al. 2011; Yin et al. 2013; Zantop et al. 2006).
The GOLDIC® procedure is a completely new approach that is based on the upregulation of several important new proteins that can directly influence the body’s own regenerative processes. One of the most important proteins of the GOLDIC procedure is plasma-Gelsolin (p-GSN). p-GSN is the longest known member of a family of actin-binding proteins. p-GSN regulates the integrity of the actin cytoskeletal structure and, therefore, influences on cell migration and proliferation and even ensures cell survival. Extensive research has been done, and more than 2000 papers are available to understand the various functions of this protein in all types of injuries, inflammatory conditions, or degenerative processes. Plasma-GSN is an important protective protein, and it prevents the toxic reaction, which occurs during cell death. Moreover, p-GSN is an important factor initiating healing process. The plasma concentration of GSN decreases during acute injury and inflammation, whereas application of recombinant gelsolin to animals improves recovery after sepsis or burn injuries (Zhang et al. 2011; Li et al. 2012). Osborn et al. showed that low serum levels of GSN correlate with the presence of gelsolin-actin complexes in synovial fluids, suggesting on local consumption of GSN in the inflamed joint. Therefore, one may assume that injection of GSN in the site of injury may improve the healing process, due to stabilization of cellular proliferative activity, and maintain the structural integrity of cells.
A study using fat-derived stem cells cultured with gelsolin and gelsolin combined with nucleotides showed its influence on cell morphology and growth pattern (Marycz et al. 2014). The lack of alteration in actin and vimentin expression after treatment with gelsolin may be a very desirable feature, as these proteins play essential role in governing the solid-like viscoelastic behavior of cells, whereas instability of cytoskeleton structure could be associated with cell disintegration. Translational research is currently addressing whether replenishment of plasma gelsolin could provide an efficacious and well-tolerated therapeutic intervention in several medical conditions.
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