Development of an innovative scalable process for the synthesis of thermosensitive hyaluronic acid hydrogels - Optimization of operational parameters and product characterization

• Grant number: 24/17064-6
• Support Opportunities: Research Grants - Innovative Research in Small Business - PIPE
• Start date: June 01, 2025
• End date: February 28, 2026
• Field of knowledge: Engineering - Chemical Engineering - Chemical Process Industries
• Principal Investigator: Maria Helena Andrade Santana
• Grantee: Maria Helena Andrade Santana
• Company: SMF Bioplus Desenvolvimento de Pesquisas Tecnológicas e Químicas Ltda. - EPP
• CNAE: Pesquisa e desenvolvimento experimental em ciências físicas e naturais
• City: Campinas
• Pesquisadores principais: Amanda Gomes Marcelino Perez ; André Delano Domingos Cavalcanti
• Associated researchers: Leonardo Kenzo Sakamoto

Abstract

The present project aims to technologically develop innovative hyaluronic acid (HA) hydrogels with thermosensitive properties for clinical applications, especially in the areas of orthopedics and regenerative medicine. The scientific literature already describes the synthesis of several types of thermosensitive hydrogels, highlighting their potential as carriers of cells and biological products, and indicating their clinical applications. However, the synthesis processes of these hydrogels that allow their transposition to a larger scale are still poorly developed.The thermosensitivity of hydrogels is achieved by binding functional molecules to specific chemical groups of the HA, modifying its structure so that it transitions from a viscous solution, at temperatures below a critical point, to a hydrogel when exposed to higher temperatures. Atypical dihydrazide (ADH), a biocompatible functional molecule metabolized by the human body, has a critical temperature close to that of the body (37°C). Thermosensitive hydrogels cross-linked with ADH (oxiAH-ADH) have already been studied as cell carriers for regeneration of the nucleus pulposus of the intervertebral disc in vitro.Previous research by the proposing team demonstrated the feasibility of the synthesis of oxiAH-ADH described in the literature, its structuring in micro and nanoparticles, and the growth of mesenchymal cells on the surface of these particles. In the conventional process, the synthesis of oxiAH-ADH hydrogels occurs in two steps: first, the high molar mass HA is partially oxidized with sodium periodate in an aqueous medium for 24 hours at room temperature, followed by dialysis for 3 days to remove excess periodate. Then, the oxidized HA is cross-linked with ADH in a rapid reaction (10 minutes) at 0°C, forming the oxiAH-ADH hydrogel. The first stage is the limiting stage of the process, and technological challenges related to the oxidation speed and removal of residual periodate are reflected in the performance of the production of the oxiAH-ADH hydrogel. These factors compromise the overall efficiency of the process and limit its scalability.The innovation proposed in this project (PIPE Phase 1) is the development of a new process for the synthesis of oxiAH-ADH hydrogels, aiming at greater efficiency and ease of scaling. The proposal is to perform the partial oxidation of the AH in the gas phase using ozone, so that there is no need to remove the residual oxidant and facilitate scaling. In this case, controlling the oxidation reaction will be the greatest challenge, and it is expected to modulate the speed and yield of the reactions through adjustments in the operational parameters. The hydrogels will be characterized by the degree of oxidation and crosslinking, which are reflected in their thermosensitivity and stability through the structural, physicochemical and rheological properties. If successful, the new process will open up prospects for the scaling and commercial production of these thermosensitive hydrogels, with applications in minimally invasive treatments for various musculoskeletal diseases. The market for this innovation is promising, considering the increasing global prevalence of musculoskeletal disorders, which impose major socioeconomic burdens and compromise patients' quality of life. (AU)