Clinical potential and challenges of using genetically modified cells for articular cartilage repair

Articular cartilage defects do not regenerate. Transplantation of autologous articular chondrocytes, which is clinically being performed since several decades, laid the foundation for the transplantation of genetically modified cells, which may serve the dual role of providing a cell population capable of chondrogenesis and an additional stimulus for targeted articular cartilage repair. Experimental data generated so far have shown that genetically modified articular chondrocytes and mesenchymal stem cells (MSC) allow for sustained transgene expression when transplanted into articular cartilage defects in vivo. Overexpression of therapeutic factors enhances the structural features of the cartilaginous repair tissue. Combined overexpression of genes with complementary mechanisms of action is also feasible, holding promises for further enhancement of articular cartilage repair. Significant benefits have been also observed in preclinical animal models that are, in principle, more appropriate to the clinical situation. Finally, there is convincing proof of concept based on a phase I clinical gene therapy study in which transduced fibroblasts were injected into the metacarpophalangeal joints of patients without adverse events. To realize the full clinical potential of this approach, issues that need to be addressed include its safety, the choice of the ideal gene vector system allowing for a long-term transgene expression, the identification of the optimal therapeutic gene(s), the transplantation without or with supportive biomaterials, and the establishment of the optimal dose of modified cells. As safe techniques for generating genetically engineered articular chondrocytes and MSCs are available, they may eventually represent new avenues for improved cell-based therapies for articular cartilage repair. This, in turn, may provide an important step toward the unanswered question of articular cartilage regeneration

PEO-PPO-PEO Tri-Block Copolymers for Gene Delivery Applications in Human Regenerative Medicine—An Overview

Lineal (poloxamers or Pluronic®) or X-shaped (poloxamines or Tetronic®) amphiphilic tri-block copolymers of poly(ethylene oxide) and poly(propylene oxide) (PEO-PPO-PEO) have been broadly explored for controlled drug delivery in different regenerative medicine approaches. The ability of these copolymers to self-assemble as micelles and to undergo sol-to-gel transitions upon heating has endowed the denomination of “smart” or “intelligent” systems. The use of PEO-PPO-PEO copolymers as gene delivery systems is a powerful emerging strategy to improve the performance of classical gene transfer vectors. This review summarizes the state of art of the application of PEO-PPO-PEO copolymers in both nonviral and viral gene transfer approaches and their potential as gene delivery systems in different regenerative medicine approaches

Supramolecular Cyclodextrin-Based Hydrogels for Controlled Gene Delivery

Controlled delivery of gene transfer vectors is a powerful strategy to enhance the temporal and spatial presentation of therapeutic agents in a defined target. Hydrogels are adapted biomaterials for gene delivery capable of acting as a localized depot of genes while maintaining the long term local availability of DNA vectors at a specific location. Supramolecular hydrogels based on cyclodextrins (CDs) have attracted considerable attention as potential biomaterials in a broad range of drug delivery applications. Their unique characteristics of thixotropicity and low cytotoxicity due to their production under mild conditions make them potential candidates to form injectable delivery systems. This work aims to provide an overview of the use of CD-based polypseudorotaxane hydrogels as controlled gene delivery systems for different applications in regenerative medicine

Application of Alginate Hydrogels for Next-Generation Articular Cartilage Regeneration

The articular cartilage has insufficient intrinsic healing abilities, and articular cartilage injuries often progress to osteoarthritis. Alginate-based scaffolds are attractive biomaterials for cartilage repair and regeneration, allowing for the delivery of cells and therapeutic drugs and gene sequences. In light of the heterogeneity of findings reporting the benefits of using alginate for cartilage regeneration, a better understanding of alginate-based systems is needed in order to improve the approaches aiming to enhance cartilage regeneration with this compound. This review provides an in-depth evaluation of the literature, focusing on the manipulation of alginate as a tool to support the processes involved in cartilage healing in order to demonstrate how such a material, used as a direct compound or combined with cell and gene therapy and with scaffold-guided gene transfer procedures, may assist cartilage regeneration in an optimal manner for future applications in patients

Joint Cartilage in Long-Duration Spaceflight

This review summarizes the current literature available on joint cartilage alterations in long-duration spaceflight. Evidence from spaceflight participants is currently limited to serum biomarker data in only a few astronauts. Findings from analogue model research, such as bed rest studies, as well as data from animal and cell research in real microgravity indicate that unloading and radiation exposure are associated with joint degeneration in terms of cartilage thinning and changes in cartilage composition. It is currently unknown how much the individual cartilage regions in the different joints of the human body will be affected on long-term missions beyond the Low Earth Orbit. Given the fact that, apart from total joint replacement or joint resurfacing, currently no treatment exists for late-stage osteoarthritis, countermeasures might be needed to avoid cartilage damage during long-duration missions. To plan countermeasures, it is important to know if and how joint cartilage and the adjacent structures, such as the subchondral bone, are affected by long-term unloading, reloading, and radiation. The use of countermeasures that put either load and shear, or other stimuli on the joints, shields them from radiation or helps by supporting cartilage physiology, or by removing oxidative stress possibly help to avoid OA in later life following long-duration space missions. There is a high demand for research on the efficacy of such countermeasures to judge their suitability for their implementation in long-duration missions

Gentherapie in der Orthopädie

Gentherapie in der Orthopädie wird intensiv im Rahmen verschiedener vererbbarer und nichtvererbbarer orthopädischer Krankheiten untersucht. Der experimentelle Fortschritt auf diesem Gebiet ist durch die Komplexität von Vektorauswahl und -herstellung, Gentransfertechnik, Applikationsweg in geeigneten Tier-Modellen sowie dem Nachweis auf struktureller und funktioneller Ebene gekennzeichnet. Die ersten klinischen Studien zur Gentherapie der chronischen Polyarthritis haben bereits ihre praktische Durchführbarkeit demonstriert. Es ist wahrscheinlich, dass genbasierte Verfahren zur Erweiterung und Verbesserung bestehender orthopädisch-chirurgischer Therapien führen werden. Schlüsselwörter Gentherapie · Gentransfer · Orthopädie · Klinische Studie

Mitochondrial Genome Editing to Treat Human Osteoarthritis—A Narrative Review

Osteoarthritis (OA) is a severe, common chronic orthopaedic disorder characterised by a degradation of the articular cartilage with an incidence that increases over years. Despite the availability of various clinical options, none can stop the irreversible progression of the disease to definitely cure OA. Various mutations have been evidenced in the mitochondrial DNA (mtDNA) of cartilage cells (chondrocytes) in OA, leading to a dysfunction of the mitochondrial oxidative phos phorylation processes that significantly contributes to OA cartilage degeneration. The mitochondrial genome, therefore, represents a central, attractive target for therapy in OA, especially using genome editing procedures. In this narrative review article, we present and discuss the current advances and breakthroughs in mitochondrial genome editing as a potential, novel treatment to overcome mtDNA-related disorders such as OA. While still in its infancy and despite a number of challenges that need to be addressed (barriers to effective and site-specific mtDNA editing and repair), such a strategy has strong value to treat human OA in the future, especially using the groundbreaking clus tered regularly interspaced short palindromic repeats (CRIPSR)/CRISPR-associated 9 (CRISPR/Cas9) technology and mitochondrial transplantation approaches

Cyst formation in the subchondral bone following cartilage repair

Subchondral bone cysts represent an early postoperative sign associated with many articular cartilage repair procedures. They may be defined as an abnormal cavity within the subchondral bone in close proximity of a treated cartilage defect with a possible communication to the joint cavity in the absence of osteoarthritis. Two synergistic mechanisms of subchondral cyst formation, the theory of internal upregulation of local proinflammatory factors, and the external hydraulic theory, are proposed to explain their occurrence. This review describes subchondral bone cysts in the context of articular cartilage repair to improve investigations of these pathological changes. It summarizes their epidemiology in both preclinical and clinical settings with a focus on individual cartilage repair procedures, examines an algorithm for subchondral bone analysis, elaborates on the underlying mechanism of subchondral cyst formation, and condenses the clinical implications and perspectives on subchondral bone cyst formation in cartilage repair

Subchondral bone remodeling patterns in larger animal models of meniscal injuries inducing knee osteoarthritis - a systematic review

Purpose Elucidating subchondral bone remodeling in preclinical models of traumatic meniscus injury may address clinically relevant questions about determinants of knee osteoarthritis (OA). Methods Studies on subchondral bone remodeling in larger animal models applying meniscal injuries as standardizing entity were systematically analyzed. Of the identifed 5367 papers reporting total or partial meniscectomy, meniscal transection or destabilization, 0.4% (in guinea pigs, rabbits, dogs, minipigs, sheep) remained eligible. Results Only early or mid-term time points were available. Larger joint sizes allow reporting higher topographical details. The most frequently reported parameters were BV/TV (61%), BMD (41%), osteophytes (41%) and subchondral bone plate thickness (39%). Subchondral bone plate microstructure is not comprehensively, subarticular spongiosa microstructure is well characterized. The subarticular spongiosa is altered shortly before the subchondral bone plate. These early changes involve degradation of subarticular trabecular elements, reduction of their number, loss of bone volume and reduced mineralization. Soon thereafter, the previously normal subchondral bone plate becomes thicker. Its porosity frst increases, then decreases. Conclusion The specifc human topographical pattern of a thinner subchondral bone plate in the region below both menisci is present solely in the larger species (partly in rabbits), but absent in rodents, an important fact to consider when designing animal studies examining subchondral consequences of meniscus damage. Large animal models are capable of providing high topographical detail, suggesting that they may represent suitable study systems refecting the clinical complexities. For advanced OA, signifcant gaps of knowledge exist. Future investigations assessing the subchondral bone in a standardized fashion are warranted