[Basement of matrix therapy in regenerative medicine by RGTA(®): From fundamental to plastic surgery]. / Les bases de la thérapie matricielle en médecine régénérative par les RGTA(®) : du fondamental à la chirurgie plastique.

Cells present continuous renewal, permitting permanent regeneration which is called tissue homeostasis. The signaling protein, known as growth factors, cytokines, interleukins and chemokines, but also the extracellular matrix play a key role in the cellular communication. All processes are deregulated after tissue injury, inducing scars. By reconstituting the extracellular matrix, it is possible to avoid the development of scar and to favorize the regeneration of the injured tissue. Glycosaminoglycans, and particularly heparan sulfates, by participating to the extracellular matrix structure, are implicated in cellular communication. This article describes how, by creating heparan sulfate mimetic or Regenerating Agent (RGTA), a French academic team has demonstrated that mammals have the ability to regenerate, by restoring the proper cellular micro-environment. After a first clinical development in two severe and chronic pathologies (corneal and skin ulcers), we show now the potential of these agents in plastic and reconstructive surgery, to regulate fibrosis and to enhance speed and quality of tissue healing.

RGTA OTR4120, a heparan sulfate mimetic, is a possible long-term active agent to heal burned skin.

Burn-related skin fibrosis leads to loss of tissue function and hypertrophic scar formation with damaging consequences for the patient. There is therefore a great need for an efficient agent to treat burned skin. We report that ReGeneraTing Agent (RGTA) reduces burn-induced skin alteration. The tissue-regenerating effect of RGTA OTR4120 was evaluated after 1-6 days and after 10 months in a rat skin burn model. This effect was also examined in vitro using fibroblasts isolated from control and 6-day-old burned skins. We measured production of dermal collagen I, III, and V and activities of metalloproteinases 2 and 9 (MMP-2 and MMP-9). Ratio of collagen III over collagen I production increased 6 days after the burn, because of a decrease in collagen I production. After 10 months, ratio of collagen III over collagen I in burn sites was still increased compared with control skin, because of an increase in collagen III production. Both abnormalities were corrected by OTR4120. OTR4120 increased pro- and active MMP-2 and MMP-9, compared with healthy and burned controls and therefore accelerated remodeling. Similar data were obtained with cultured fibroblasts from healthy and burned skins. OTR4120 enhanced healing in short- and long-term after burns, reducing the formation of fibrotic tissue, and then represents a potential agent to improve burned skin healing.

Matrix therapy in regenerative medicine, a new approach to chronic wound healing.

Nonhealing wounds remain a major health problem whose treatment is challenging and costly. Treatments based on cells or growth factors are still not very effective. We developed an entirely novel strategy consisting in treatment of the wound-tissue matrix with biopolymers engineered to mimic heparan sulfates called OTR4120. This compound was dextran polymer with sulfated and carboxymethyl groupments. After binding to matrix proteins, the heparan-sulfate-mimicking polymer protects the microenvironment, maintaining the normal production of signals and growth factors needed for healing to occur. Here, we show that a specific biopolymer accelerates ulcer closure and improves re-epithelialization and dermal-matrix-component remodeling. OTR4120 treatment was associated with faster maturation of epidermal structures, most notably regarding the number of epithelial-cell layers, and with an appearance that more closely resembled normal skin. Treatment had also a main effect on collagen I and III expression. Necrotic skin ulcers induced in mice with doxorubicin recovered normal collagen levels and organization, with no evidence of fibrosis. Thus, appropriate polymer-based matrix therapy is a valid and simple alternative to regenerative medicine.