Thermo-Responsive Hyaluronan-Based Hydrogels Combined with Allogeneic Cytotherapeutics for the Treatment of Osteoarthritis

Abstract

Thermo-responsive hyaluronan-based hydrogels and FE002 human primary chondroprogenitor cell sources have both been previously proposed as modern therapeutic options for the management of osteoarthritis (OA). For the translational development of a potential orthopedic combination product based on both technologies, respective technical aspects required further optimization phases (e.g., hydrogel synthesis upscaling and sterilization, FE002 cytotherapeutic material stabilization). The first aim of the present study was to perform multi-step in vitro characterization of several combination product formulas throughout the established and the optimized manufacturing workflows, with a strong focus set on critical functional parameters. The second aim of the present study was to assess the applicability and the efficacy of the considered combination product prototypes in a rodent model of knee OA. Specific characterization results (i.e., spectral analysis, rheology, tribology, injectability, degradation assays, in vitro biocompatibility) of hyaluronan-based hydrogels modified with sulfo-dibenzocyclooctyne-PEG4-amine linkers and poly(N-isopropylacrylamide) (HA-L-PNIPAM) containing lyophilized FE002 human chondroprogenitors confirmed the suitability of the considered combination product components. Specifically, significantly enhanced resistance toward oxidative and enzymatic degradation was shown in vitro for the studied injectable combination product prototypes. Furthermore, extensive multi-parametric (i.e., tomography, histology, scoring) in vivo investigation of the effects of FE002 cell-laden HA-L-PNIPAM hydrogels in a rodent model revealed no general or local iatrogenic adverse effects, whereas it did reveal some beneficial trends against the development of knee OA. Overall, the present study addressed key aspects of the preclinical development process for novel biologically-based orthopedic combination products and shall serve as a robust methodological basis for further translational investigation and clinical work.

Injectable Hyaluronan-Based Thermoresponsive Hydrogels for Dermatological Applications

“…HA-L-pNIPAM copolymers (HA-L-pNIPAM 0.10 , HA-L-pNIPAM 0.25 , HA-L-pNIPAM 0.50 ) were synthesized using a slightly modified procedure based on a previous publication [ 33 , 34 ]. The scheme for the green chemistry synthetic route of the HA-L-pNIPAM copolymers is presented in Supplementary Materials (Figure S1) .…”

“…Recently, a novel technology that involved a specific conjugation of the thermoresponsive polymer, poly(N-Isopropylacrylamide) (pNIPAM), to the linear HA backbone via a cyclooctyne linker (L) was reported [ 33 , 34 ]. Due to the desolvatation of the hydrophobic pNIPAM moieties above a defined lower critical solution temperature (LCST) and to the presence of the linker, the synthetic HA-L-pNIPAM copolymer spontaneously forms submicron spherical particles above the LCST [ 33 , 34 , 35 , 36 ]. These domains act as inter-chain crosslinkers, resulting in a sol–gel copolymer transition driven only by physical interactions, avoiding the use of chemical cross-linking agents.…”

Autologous and Allogeneic Cytotherapies for Large Knee (Osteo)Chondral Defects: Manufacturing Process Benchmarking and Parallel Functional Qualification

“…Specifically, extensive technical work has validated the applicability of such cells in industrial-scale manufacturing workflows for transposition to GMP manufacturing [ 50 ]. Furthermore, previous preclinical research has shown the versatility and high potential of FE002 primary chondroprogenitors as promising contenders in cell-based orthopedic regenerative medicine [ 50 , 51 , 52 , 53 , 54 , 81 ]. Some of the advantages of using such an allogeneic cellular active substance for cartilage bioengineering involve the off-the-freezer availability of standardized biologicals, rationalized manufacturing workflows, and drastically reduced operative burdens [ 50 ].…”

“…As previously mentioned, a large body of scientific and technical research regarding the clinical-grade allogeneic FE002 primary chondroprogenitor cell source is currently available. Notably, the in vitro and in vivo safety of the FE002 cells has been studied and validated by several research groups [ 50 , 51 , 52 , 53 , 54 ]. Based on the presented technical data and the current clinical developments of autologous and allogeneic cell-based solutions for knee chondral lesion management, a pilot clinical trial is being devised around the therapeutic FE002 progenitor cell source.…”

“…Specifically, the studied autologous chondral graft is indicated for large ICRS grade III or IV localized and symptomatic knee cartilage lesions [ 4 , 48 ]. Parallelly to this autologous approach, multifaceted translational work was carried out under the Swiss progenitor cell transplantation program for the eventual cytotherapeutic use of allogeneic primary chondroprogenitors (i.e., FE002 clinical-grade cells) in human orthopedics [ 49 , 50 , 51 , 52 , 53 , 54 ]. Given that both tissue engineering approaches share technical, clinical, and regulatory similarities, both options are currently being locally investigated [ 48 , 50 ].…”