A Retrospective Self-Controlled Study Evaluating the Prophylactic Effects of CACIPLIQ20 on Postsurgical Scars.

Background: CACIPLIQ20 (OTR3, Paris, France) is a medical device used for the treatment of chronic skin ulcers. It contains a heparan sulfate mimetic that accelerates tissue healing by stabilizing matrix proteins and protecting heparin-binding growth factors. In humans, an open self-controlled study suggested that the topical application of CACIPLIQ20 optimizes skin healing following surgery. Objectives: To expand previous findings using a different CACIPLIQ20 administration regimen. Methods: Twenty-four females were referred for breast-reduction surgery. Each patient had their own control with 1 CACIPLIQ20-treated and 1 saline-treated control breast. The treated side (right or left) was randomly assigned by the operating surgeon. Scar appearance was assessed by 6 independent raters using a global visual scar comparison scale based on scar photographs. All raters were blinded toward the CACIPLIQ20-treated side. Results: The follow-up period following surgery ranged from 1 to 12 months with a median follow-up of 6 months. Overall, there was a mean improvement of 15.2% (SD = 26.7) in favor of CACIPLIQ20 (P = .016). On the CACIPLIQ20-treated side, the mean score per patient was above 20% in 11 patients and above 30% improvement in 8 cases. In contrast, only 3 patients were considered improved by at least 20% on the control side and only 1 above 30%. A comparison of different application regimens suggested that the best trend was obtained with a single administration of CACIPLIQ20 at Day 0. Conclusions: In conclusion, CACIPLIQ20 could represent an interesting scar prophylactic therapy, based on a single administration at the time of surgery, and without any known adverse effects.

Protective Effects of a synthetic glycosaminoglycan mimetic (OTR4132) in a rat immunotoxic lesion model of septohippocampal cholinergic degeneration.

Using a partial hippocampal cholinergic denervation model, we assessed the effects of the RGTA® named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial septum/diagonal band of Broca (0.37 µg); vehicle injections served as controls. Immediately after surgery, OTR4132 was injected into the lateral ventricles (0.25 µg/5 µl/rat) or intramuscularly (1.5 mg/kg). To determine whether OTR4132 reached the lesion site, some rats received intracerebroventricular (ICV) or intramuscular (I.M.) injections of fluorescent OTR4132. Rats were sacrificed at 4, 10, 20, or 60 days post-lesion (DPL). Fluorescein-labeled OTR4132 injected ICV or I.M. was found in the lesion from 4 to 20 DPL. Rats with partial hippocampal cholinergic denervation showed decreases in hippocampal acetylcholinesterase reaction products and in choline acetyltransferase-positive neurons in the medial septum. These lesions were the largest at 10 DPL and then remained stable until 60 DPL. Both hippocampal acetylcholinesterase reaction products and choline acetyltransferase-positive neurons in the medial septum effects were significantly attenuated in OTR4132-treated rats. These effects were not related to competition between OTR4132 and 192 IgG-saporin for the neurotrophin receptor P75 (p75NTR), as OTR4132 treatment did not alter the internalization of Cy3-labelled 192 IgG. OTR4132 was more efficient at reducing the acetylcholinesterase reaction products and choline acetyltransferase-positive neurons than a comparable heparin dose used as a comparator. Using the slice superfusion technique, we found that the lesion-induced decrease in muscarinic autoreceptor sensitivity was abolished by intramuscular OTR4132. After partial cholinergic damage, OTR4132 was able to concentrate at the brain lesion site possibly due to the disruption of the blood-brain barrier and to exert structural and functional effects that hold promises for neuroprotection/neurotrophism.

Immunothrombotic dysregulation in chagas disease and COVID-19: a comparative study of anticoagulation.

Chagas and COVID-19 are diseases caused by Trypanosoma cruzi and SARS-CoV-2, respectively. These diseases present very different etiological agents despite showing similarities such as susceptibility/risk factors, pathogen-associated molecular patterns (PAMPs), recognition of glycosaminoglycans, inflammation, vascular leakage hypercoagulability, microthrombosis, and endotheliopathy; all of which suggest, in part, treatments with similar principles. Here, both diseases are compared, focusing mainly on the characteristics related to dysregulated immunothrombosis. Given the in-depth investigation of molecules and mechanisms related to microthrombosis in COVID-19, it is necessary to reconsider a prompt treatment of Chagas disease with oral anticoagulants.

ReGeneraTing Agents (rgta®) technology combined with antibiotics improves outcomes for infections in the upper limb.

A matrix therapy agent marketed as CACIPLIQ20® showed marked improvement in the healing rate of hand infections, including functional recovery. It can be used at both earlier and later stages to promote faster healing and prevent an adverse outcome.

Matrix therapy is a cost-effective solution to reduce amputation risk and improve quality of life: pilot and case studies.

INTRODUCTION: Chronic, non-healing ulcers remain one of the most challenging clinical situations for health care practitioners. Often, conventional treatments fail and lead to amputation, further decreasing the patient's quality of life and resulting in enormous medical expenditures for healthcare systems. Here we evaluated the use of and cost-effectiveness of the RGTA (ReGeneraTing Agents) medical device CACIPLIQ20 (OTR4120) for chronic lower-extremity ulcers in patients with Leriche and Fontaine Stage IV peripheral arterial disease who were not eligible for revascularization. METHODS: This uncontrolled pilot study included 14 chronic lower extremity ulcers in 12 patients in one hospital. The pilot study included 12 patients with TcPO2 < 20 mm Hg and ABPI < 0.5 who had either a minimum of one chronic lower extremity ulcer or a chronic ulcer related to amputation. OTR4120 was applied twice a week or until complete healing, for up to 12 weeks. Ulcer surface area reduction (%)after 2, 4, 8 and 12 weeks, appearance after 4 weeks, and healing after 12 weeks were measured and recorded. RESULTS: A 35% reduction in ulcer size was achieved after 4 weeks. 7 (50%) out of 14 ulcers completely healed within 1 to 3 months of treatment. DISCUSSION: OTR4120 is an effective therapeutic option for patients with chronic lower extremity ulcers, can provide major improvement of quality of life and has the added benefit of being a significant cost-effective solution for healthcare systems.

Case Reports for Topical Treatment of Corneal Ulcers with a New Matrix Therapy Agent or RGTA® in Dogs.

Superficial corneal ulcers that fail to heal within a normal time period and are refractory to conventional therapy in dogs are common in veterinary practice. Different etiologies can lead to this result, including spontaneous chronic corneal epithelial defects (SCCEDs) and ulcerative keratitis associated with bullous keratopathy. Thus, there is an urgent need to find new therapeutic approaches such as matrix therapy replacement. To determine the efficacy of a new ophthalmic treatment (Clerapliq®) for SCCEDs and ulcerative keratitis associated with bullous keratopathy, a total of 11 dogs referred to the clinic because of nonhealing erosive ulcers after a classic primary treatment were enrolled to get this new treatment. Dogs underwent ophthalmic exams and 7 dogs (10 eyes) were diagnosed with superficial ulceration and 4 dogs (5 eyes) with bullous keratopathy due to endothelial dystrophy/degeneration. They received eye drops of Clerapliq® every 3 days until recovery. The results showed that the corneas with recurrences of the ulcers were resolved predominantly by using Clerapliq® every 3 days in 83.3% of the cases during a period of treatment ranging between 6 to 35 days. Therefore, this new approach using matrix therapy regenerating technology in treating superficial ulcers and bullous keratopathy in dogs can be successfully considered as an adjunctive therapy.

Heparan Sulfate Mimetics Accelerate Postinjury Skeletal Muscle Regeneration.

Although skeletal muscle is capable of complete recovery after an injury, specific situations require support or acceleration of this process, such as in the elderly and athletes, respectively. Skeletal muscle regeneration is due to muscle stem cells (MuSCs) that undergo adult myogenesis, a process sustained by MuSC environment. Although recognized as important, extracellular matrix (ECM) has been overlooked in this process. Matrix-based therapy aims at improving ECM remodeling to support tissue repair. In this context, we investigated the properties of a single injection of the clinical grade glycosaminoglycan mimetics RGTA® (ReGeneraTing Agents) on skeletal muscle regeneration in a context compatible with a clinical application, that is, 3 days after the injury. Our results show that RGTA-treated muscles showed an increase of the number of myonuclei in regenerating myofibers and an increase of the capillarization of the new myofibers. In vitro experiments showed that RGTA directly acts on MuSCs by stimulating their fusion into myotubes and on endothelial cells by stimulating the formation and maturation of vessels in a 3D culture setup. These results indicate that a single administration of RGTA in regenerating muscle stimulated both myogenesis and angiogenesis, thus accelerating skeletal muscle regeneration. Impact Statement Although highly powerful in normal condition, postinjury skeletal muscle regeneration is less efficient in some situations, such as obese, elderly, or resting people. In other context, such as high-performance sport, skeletal muscle regeneration must be shortened but in a way ensuring a full functional recovery. In this context, our results show that a single injection of the clinical grade glycosaminoglycan mimetics RGTA® (ReGeneraTing Agents), in a context compatible with a clinical application, that is, 3 days after the injury, is beneficial for skeletal muscle regeneration, through the stimulation of both myogenesis and angiogenesis.

ReGeneraTing Agents (RGTA®): A new option for healing and improving treatment outcomes for traumatic and burn injuries of the hand.

CACIPLIQ20® significantly improved the outcomes of severe burn injuries of the hand. Healing was accelerated, with little or no scarring, allowing for greater mobility over the joints and maintained suppleness. Functional recovery was achieved in all cases.

Heparan Sulfate Mimetics: A New Way to Optimize Therapeutic Effects of Hydrogel-Embedded Mesenchymal Stromal Cells in Colonic Radiation-Induced Damage.

Clinical expression of gastrointestinal radiation toxicity on non-cancerous tissue could be very life threatening and clinicians must deal increasingly with the management of late side effects of radiotherapy. Cell therapy, in particular mesenchymal stromal cell (MSC) therapy, has shown promising results in numerous preclinical animal studies and thus has emerged as a new hope for patient refractory to current treatments. However, many stem cell clinical trials do not confer any beneficial effect suggesting a real need to accelerate research towards the successful clinical application of stem cell therapy. In this study, we propose a new concept to improve the procedure of MSC-based treatment for greater efficacy and clinical translatability. We demonstrated that heparan sulfate mimetic (HS-m) injections that restore the extracellular matrix network and enhance the biological activity of growth factors, associated with local injection of MSC protected in a hydrogel, that increase cell engraftment and cell survival, improve the therapeutic benefit of MSC treatment in two animal models relevant of the human pathology. For the first time, a decrease of the injury score in the ulcerated area was observed with this combined treatment. We also demonstrated that the combined treatment favored the epithelial regenerative process. In this study, we identified a new way, clinically applicable, to optimize stem-cell therapy and could be proposed to patients suffering from severe colonic defect after radiotherapy.

ReGeneraTing Agents (RGTA®) are a new option to improve amputation outcomes in the recovery of severe hand injuries.

CACIPLIQ20® was used to accelerate the healing process and stimulate the viability of flaps and skin grafts, thereby improving amputation outcomes. An excellent range of motion was achieved with hardly any contracture or scarring. Pain relief and reduced sensitivity was noted, while healing of bone and tendon also improved, resulting in functional recovery.

Periodontal reconstruction by heparan sulfate mimetic-based matrix therapy in Porphyromonas gingivalis-infected mice.

BACKGROUND: Periodontitis is a set of chronic inflammatory diseases affecting the supporting structures of the teeth, during which a persistent release of lytic enzymes and inflammatory mediators causes a self-perpetuating vicious cycle of tissue destruction and repair. A matrix-based therapy using a heparan sulfate (HS) analogue called ReGeneraTing Agent (RGTA) replaces destroyed HS by binding to available heparin-binding sites of structural molecules, leading to restoration of tissue homeostasis in several inflammatory tissue injuries, including a hamster periodontitis model. METHODS: The ability of RGTA to restore the periodontium was tested in a model of Porphyromonas gingivalis-infected Balb/cByJ mice. After 12 weeks of disease induction, mice were treated weekly with saline or RGTA (1.5 mg/kg) for 8 weeks. Data were analyzed by histomorphometry. RESULTS: RGTA treatment restored macroscopic bone loss. This was related to (1) a significant reduction in gingival inflammation assessed by a decrease in infiltrated connective tissue, particularly in cells expressing interleukin 1ß, an inflammatory mediator selected as a marker of inflammation; (2) a normalization of bone resorption parameters, i.e. number, activation and activity of osteoclasts, and number of preosteoclasts; (3) a powerful bone formation reaction. The Sharpey's fibers of the periodontal ligament recovered their alkaline phosphatase coating. This was obtained while P. gingivalis infection was maintained throughout the treatment period. CONCLUSIONS: RGTA treatment was able to control the chronic inflammation characteristic of periodontitis and blocked destruction of periodontal structures. It ensured tissue regeneration with recovery of the periodontium's anatomy.

Evaluation of a new matrix regenerating agent in patients with Sjögren syndrome and superficial ulcerative keratitis resistant to conventional therapy: A report of 3 cases.

RATIONALE: Sjögren syndrome (SS) is frequently associated with ulcerative keratitis, which is difficult to treat due to lacrimal tear deficiency and inflammation of the ocular surface. PATIENT CONCERNS: We report the successful additive effect of a matrix regenerating agent (RGTA, Cacicol) in SS patients with severe superficial ulcerative keratitis resistant to conventional therapy. DIAGNOSES: Retrospective, noncomparative case series of patients with primary or secondary SS associated with chronic diffuse keratitis. INTERVENTIONS: All patients (3 women, aged 46, 59, and 84 years) had several years of dry-eye disease history and recurrent keratitis despite having used maximal dose topical therapies including artificial tear substitutes, topical vitamin A, and cyclosporine 0.05% emulsion. All patients suffered from dry, diffuse, and chronic superficial keratitis of at least 75% of the corneal surface, with no sign of corneal neovascularization or opacity. OUTCOMES: RGTA treatment led to a rapid and marked decrease of ocular pain, burning, irritation, foreign body sensation, and improvement of visual acuity. Total diffuse keratitis healing occurred after several months of treatment. Discontinuation of RGTA administration led to the recurrence of severe keratitis; re-introduction of RGTA was successful. No local or systemic adverse effects related to treatment were reported. LESSONS: RGTA treatment was effective and safe in this small series of 3 patients suffering from SS associated with recurrent or chronic superficial ulcerative keratitis resistant to conventional therapy.

Randomized controlled trial demonstrates the benefit of RGTA® based matrix therapy to treat tendinopathies in racing horses.

A randomized controlled trial was performed on racing horses, to evaluate the efficacy of a new class of therapeutic agents in regenerative medicine-ReGeneraTing Agents® (RGTA®), to treat tendinopathies. Preliminary uncontrolled studies on tendon healing in racing horses with RGTA® (OTR4131)-Equitend® showed encouraging results, justifying performing a randomized, controlled, multicenter study with a two-year racing performance follow up. The objective of this study was to evaluate the effect of Equitend® versus placebo on acute superficial digital flexor tendonitis in racing French Standardbred Trotters (ST). Twenty-two ST were randomly and blindly assigned to receive with a ratio of 2 to 1, a single Equitend® (n = 14) or placebo (n = 8) intralesional injection under ultrasonographic guidance. Horses were evaluated over 4 months, by clinical and ultrasonographic evaluations (day 0, months 1, 2, 4), and their racing performances followed up over the 2 years after treatment. During the first month of treatment, a significant decrease in the cross-sectional area (CSA) was found in the Equitend® group (p = 0.04). After 4 months, the number of Equitend® treated horses with an improved CSA was significantly higher than the placebo-treated horses (p = 0.03571). The Equitend® group returned to their pre-injury performance level, racing in, and winning, significantly more races than the placebo group (p = 0.01399 and 0.0421, respectively). Furthermore, recurrence was significantly higher in the placebo group than in the Equitend® group (71.4% vs 16.6%, p = 0.02442). In conclusion, we measured a significant, short-term, reduction effect on CSA and demonstrated a long-term beneficial effect of intralesional injection of Equitend® for the treatment of superficial digital flexor tendonitis on racing ST, racing 2. 3 times more often than placebo, with 3.3 times fewer recurrences maintaining pre-injury performance level. This study may open the way for the development of a human treatment of tendonitis.

A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke.

Alteration of the extracellular matrix (ECM) is one of the major events in the pathogenesis of brain lesions following ischemic stroke. Heparan sulfate mimetics (HSm) are synthetic pharmacologically active polysaccharides that promote ECM remodeling and tissue regeneration in various types of lesions. HSm bind to growth factors, protect them from enzymatic degradation and increase their bioavailability, which promotes tissue repair. As the ECM is altered during stroke and HSm have been shown to restore the ECM, we investigated the potential of HSm4131 (also named RGTA-4131®) to protect brain tissue and promote regeneration and plasticity after a stroke. Methods: Ischemic stroke was induced in rats using transient (1 h) intraluminal middle cerebral artery occlusion (MCAo). Animals were assigned to the treatment (HSm4131; 0.1, 0.5, 1.5, or 5 mg/kg) or vehicle control (saline) groups at different times (1, 2.5 or 6 h) after MCAo. Brain damage was assessed by MRI for the acute (2 days) and chronic (14 days) phases post-occlusion. Functional deficits were evaluated with a battery of sensorimotor behavioral tests. HSm4131-99mTc biodistribution in the ischemic brain was analyzed between 5 min and 3 h following middle cerebral artery reperfusion. Heparan sulfate distribution and cellular reactions, including angiogenesis and neurogenesis, were evaluated by immunohistochemistry, and growth factor gene expression (VEGF-A, Ang-2) was quantified by RT-PCR. Results: HSm4131, administered intravenously after stroke induction, located and remained in the ischemic hemisphere. HSm4131 conferred long-lasting neuroprotection, and significantly reduced functional deficits with no alteration of physiological parameters. It also restored the ECM, and increased brain plasticity processes, i.e., angiogenesis and neurogenesis, in the affected brain hemisphere. Conclusion: HSm represent a promising ECM-based therapeutic strategy to protect and repair the brain after a stroke and favor functional recovery.

A New Matrix Therapy Agent for Faster Corneal Healing and Less Ocular Discomfort Following Epi-off Accelerated Corneal Cross-linking in Progressive Keratoconus.

PURPOSE: To investigate the hypothesis that a new matrix therapy agent (ReGeneraTing Agent, [RGTA]) would speed up the corneal reepithelialization, improve stromal healing, and reduce ocular symptoms after epi-off corneal cross-linking (CXL). METHODS: Sixty eyes of 60 patients with progressive keratoconus were enrolled in the study. Epi-off accelerated CXL was performed in all patients. Sixty eyes were randomized into two groups according to use of RGTA eye drops prior to contact lens fitting at the end. Identical medical agents were started postoperatively for the two groups. All participants were monitored on 3 consecutive days after the CXL. Ocular pain, burning, stinging, tearing, photophobia, conjunctival hyperemia, and corneal healing status were evaluated. RESULTS: By day 2, 25 eyes (83.3%) with RGTA revealed complete healing compared to 4 eyes (13.3%) that revealed complete healing in the control group (P < .001). All eyes had complete corneal epithelial defect closure by day 3 in both groups. Ocular pain scores were lower in the RGTA group on days 0, 1, and 2 (all P < .05). Burning scores were lower on days 1 and 2; stinging scores on days 2 and 3; tearing scores on days 2 and 3; and photophobia on days 1 and 2 (P < .05) in the RGTA group compared to the control group. CONCLUSIONS: RGTA ophthalmic solution facilitates corneal healing by reconstructing the extracellular matrix in the wound area, leading to an earlier relief of symptoms for patients. [J Refract Surg. 2017;33(3):163-170.].

RGTA® or ReGeneraTing Agents mimic heparan sulfate in regenerative medicine: from concept to curing patients.

The importance of extracellular matrix (ECM) integrity in maintaining normal tissue function is highlighted by numerous pathologies and situations of acute and chronic injury associated with dysregulation or destruction of ECM components. Heparan sulfate (HS) is a key component of the ECM, where it fulfils important functions associated with tissue homeostasis. Its degradation following tissue injury disrupts this delicate equilibrium and may impair the wound healing process. ReGeneraTing Agents (RGTA®s) are polysaccharides specifically designed to replace degraded HS in injured tissues. The unique properties of RGTA® (resistance to degradation, binding and protection of ECM structural and signaling proteins, like HS) permit the reconstruction of the ECM, restoring both structural and biochemical functions to this essential substrate, and facilitating the processes of tissue repair and regeneration. Here, we review 25 years of research surrounding this HS mimic, supporting the mode of action, pre-clinical studies and therapeutic efficacy of RGTA® in the clinic, and discuss the potential of RGTA® in new branches of regenerative medicine.

RGTA®-based matrix therapy - A new branch of regenerative medicine in locomotion.

Matrix therapy is an innovative, minimally invasive approach in the field of regenerative medicine, that aims to promote tissue regeneration by reconstructing the cellular microenvironment following tissue injury. This approach has significant therapeutic potential in the treatment of pathologies characterized by tissue inflammation and damage, or following injury, conditions which can be incapacitating and cost-consuming. Heparan sulfate mimics, termed ReGeneraTing Agents (RGTA®s) have emerged as a unifying approach to treat these diverse pathologies. Today, skin and corneal healing topical products have already been used in clinics, demonstrating a proof of concept in humans. In this review, we present key evidence that RGTA®s regenerate damaged tissue in bone, muscle, tendon and nerve, with astonishing results. In animal models of bone surgical defects and inflammatory bone loss, RGTA® induced healing of injured bones by controlling inflammation and bone resorption, and stimulated bone formation by coordinating vascularization, recruitment and differentiation of competent cells from specific niches, restoring tissue quality to that of uninjured tissue, evoking true regeneration. In models of muscle injury, RGTA® had marked effects on healing speed and quality, evidenced by increased muscle fiber density, maturation, vascularization and reduced fibrosis, more mature motor endplates and functional recovery. Applications merging RGTA®-based matrix therapy and cell therapy, combining Extra-Cellular Matrix reconstruction with cells required for optimal tissue repair show significant promise. Hence restoration of the proper microenvironment is a new paradigm in regenerative medicine. Harnessing the potential of RGTA® in this brave, new vision of regenerative therapy will therefore be the focus of future studies.

Refractory sickle cell leg ulcer: is heparan sulphate a new hope?

Patients with sickle cell disease are known to have recurrent lower extremity ulcers that have a high pain score and are resistant to conventional means of wound therapy. This study reports the successful use of synthetic heparan sulphate (Cacipliq20(®) , OTR3, Paris, France) in the treatment of a sickle cell ulcer that had failed to respond to several other means of treatment. Therapeutic success was assessed by complete wound coverage and vast improvement in pain score. This is the first study to report use of heparan sulphate in sickle cell ulcers.

ReGeneraTing agents matrix therapy regenerates a functional root attachment in hamsters with periodontitis.

Matrix-based therapy restoring the cell microenvironment is a new approach in regenerative medicine successfully treating human chronic pathologies by using a heparan sulfate mimetic (ReGeneraTing agents [RGTA]). Periodontitis are inflammatory diseases destroying the tooth-supporting tissues with no satisfactory therapy. We studied in vivo RGTA ability to fully restore the tooth-supporting tissues. After periodontitis induction, hamsters were treated with RGTA (1.5 mg kg(-1) w(-1)) or saline. Bone loss was evaluated and immunohistochemical labeling of molecules expressed during cementum development was performed. RGTA treatment restored alveolar bone and the attachment apparatus where fibers were inserted in acellular decorin-negative cementum. RGTA treatment increased the epithelial rests of Malassez, previously depleted by periodontitis. Bone morphogenetic protein (BMP) expressions were compartmentalized: BMP-3 was strongly expressed by epithelial rests of Malassez; BMP-7 was expressed by cells lying on the cementum and BMP-2 by osteoprogenitors around bone formation sites but not at the root-bone interface. Cells near the cementum and bone expressed the ALK2 receptor. This is the first evidence that reconstructing the extracellular matrix scaffold with a heparan sulfate mimetic regenerated the root interface despite the persistence of the bacteria responsible for the disease The improved cellular microenvironment led to the sequential recruitment of cell populations involved in attachment apparatus regeneration.