Combination of Hyaluronan and Lyophilized Progenitor Cell Derivatives: Stabilization of Functional Hydrogel Products for Therapeutic Management of Tendinous Tissue Disorders

Abstract

Cultured progenitor cells and derivatives have been used in various homologous applications of cutaneous and musculoskeletal regenerative medicine. Active pharmaceutical ingredients (API) in the form of progenitor cell derivatives such as lysates and lyophilizates were shown to retain function in controlled cellular models of wound repair. On the other hand, hyaluronan-based hydrogels are widely used as functional vehicles in therapeutic products for tendon tissue disorders. The aim of this study was the experimental characterization of formulations containing progenitor tenocyte-derived APIs and hyaluronan, for the assessment of ingredient compatibility and stability in view of eventual therapeutic applications in tendinopathies. Lyophilized APIs were determined to contain relatively low quantities of proteins and growth factors, while being physicochemically stable and possessing significant intrinsic antioxidant properties. Physical and rheological quantifications of the combination formulas were performed after hydrogen peroxide challenge, outlining significantly improved evolutive viscoelasticity values in accelerated degradation settings. Thus, potent effects of physicochemical protection or stability enhancement of hyaluronan by the incorporated APIs were observed. Finally, combination formulas were found to be easily injectable into ex vivo tendon tissues, confirming their compatibility with further translational clinical approaches. Overall, this study provides the technical bases for the development of progenitor tenocyte derivative-based injectable therapeutic products or devices, to potentially be applied in tendinous tissue disorders.

Nanoforming Hyaluronan-Based Thermoresponsive Hydrogels: Optimized and Tunable Functionality in Osteoarthritis Management

“…Due to the aforementioned factors potentially hindering the efficacy of HA-based injectable OA formulations, several chemical derivatization strategies (e.g., crosslinking, chemical functionalization, combinations) have been investigated to reduce multifactorial degradation and maximize hydrogel residence time [ 15 , 19 , 20 , 21 , 22 , 23 , 24 ]. Specific HA conjugates comprising the thermoresponsive polymer poly( N -isopropylacrylamide) (PNIPAM) and a linker were recently proposed [ 20 , 25 ].…”

Industrial Biotechnology Conservation Processes: Similarities with Natural Long-Term Preservation of Biological Organisms

“…Despite relatively high equipment and operating costs, freeze-drying has been widely adopted in research (i.e., biological strain preservation), medical (i.e., tissue transplant storage or therapeutic product formulation), and industrial fields (e.g., food processing and preservation optimization) [ 18 , 35 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. Specific activities or contexts and the large-scale demand for optimized material packaging and transport modalities have historically driven the technical development in the field of lyophilization (e.g., preparation of penicillin or blood products for soldiers, food for astronauts, etc.).…”

“…Despite the maintenance of most cellular structures in optimal drying conditions, the different water phase transitions and water movements during lyophilization processing often prove detrimental to the cells with regard to viability maintenance ( Table 2 ). However, many types of biological derivatives may be efficiently lyophilized and are able to retain appropriate biological or physical/chemical functions, despite viability loss for the cells [ 12 , 35 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. Such results obtained by the authors and others have favored the investigation of cell-derived cell-free biological entities or complexes, which may bare several technical, therapeutic, logistical, or regulatory advantages as compared to classical cytotherapies using fresh living cells, for example ( Figure 1 ) [ 12 , 65 , 71 ].…”

“…However, many types of biological derivatives may be efficiently lyophilized and are able to retain appropriate biological or physical/chemical functions, despite viability loss for the cells [ 12 , 35 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. Such results obtained by the authors and others have favored the investigation of cell-derived cell-free biological entities or complexes, which may bare several technical, therapeutic, logistical, or regulatory advantages as compared to classical cytotherapies using fresh living cells, for example ( Figure 1 ) [ 12 , 65 , 71 ]. This approach has notably enabled progenitor cellular extract long-term storage and reconstitution in a wide variety of appropriate pharmaceutical preparations for investigational clinical use (e.g., hyaluronan-based hydrogels, oil-in-water creams or ointments) under the Swiss progenitor cell transplantation program ( Figure 1 ).…”

Process Optimization and Efficacy Assessment of Standardized PRP for Tendinopathies in Sports Medicine: Retrospective Study of Clinical Files and GMP Manufacturing Records in a Swiss University Hospital

“…Furthermore, diverse regenerative medicine approaches have recently been investigated to improve tendinopathy management, including stem cell therapies, tissue graft bioengineering, and the use of orthobiologics [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Notably, recent regulatory shifts and quality-oriented constraints related to cytotherapies have prompted the deployment of important efforts toward the development of cell-derived and cell-free therapeutic management options for tendinopathies [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Parallelly, the medical use of autologous platelet-rich plasma (PRP) preparations in orthopedics and in sports medicine for tendon and ligament affections has drastically increased over the past two decades [ 23 , 24 , 25 , 26 , 27 ].…”