Trends in clinical trials for articular cartilage repair by cell therapy

Negoro, Takaharu; Takagaki, Yuri; Okura, Hanayuki; Matsuyama, Akifumi

doi:10.1038/s41536-018-0055-2

Cited by 84 publications

(83 citation statements)

References 20 publications

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Section: Discussionmentioning

confidence: 99%

“…Limitations with ACh-based therapies for cartilage repair are driving investment into therapies that utilize BMSCs or other cell populations [29]. The most commonly evaluated alternative cell populations are bone marrow-derived cells (31%, including BMSCs) [29]. However, the progression of prospective therapies using bone marrow-derived cells to phase III trials is low (3.2% [29]), and no BMSC cartilage repair therapies have attained FDA approval.…”

Section: Discussionmentioning

confidence: 99%

“…The most commonly evaluated alternative cell populations are bone marrow-derived cells (31%, including BMSCs) [29]. However, the progression of prospective therapies using bone marrow-derived cells to phase III trials is low (3.2% [29]), and no BMSC cartilage repair therapies have attained FDA approval. We reason that significant knowledge gaps in the understanding of BMSC chondrogenic differentiation play a major role in the failure of BMSCs to achieve cartilage repair expectations [1].…”

Section: Discussionmentioning

confidence: 99%

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Micro-pellet culture reveals that bone marrow mesenchymal stromal cell (BMSC) chondrogenic induction is triggered by a single day of TGF-β1 exposure

Futrega

Robey

Crawford

et al. 2019

Preprint

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Despite immense promise, engineering of stable cartilage tissue from bone marrow-derived stromal cells (BMSCs, also known as bone marrow-derived "mesenchymal stem cells") remains elusive. Relative cartilage-like matrix deposition is commonly used to guide BMSC chondrogenic optimisation efforts. However, matrix deposition is heterogeneous in most models, and notably, it lags behind cell fate decisions. We reason that the lag time between cell fate decision and matrix accumulation, coupled with matrix heterogeneity, has obscured basic BMSC biological characteristics, such as differentiation kinetics. Here, we utilize a customized microwell platform to assemble hundreds of small-diameter BMSC micro-pellets and characterized chondrogenic differentiation kinetics in response to the canonical signaling molecule, transforming growth factor-b1 (TGF-b1). Micro-pellets provide a homogeneous readout, and our experimental design accounts for the significant time delay between growth factor signal and deposition of cartilage-like matrix. While 14-to-21-day induction protocols are routine, BMSC micro-pellet cultures reveal that a single day of TGF-b1 exposure was sufficient to trigger chondrogenic differentiation cascades resulting in outcomes similar to micro-pellets exposed to TGF-b1 for 21 days. RNA-sequencing analysis demonstrated that one day of TGF-b1 exposure was also sufficient to induce hypertrophic cascades in BMSC, not observed in articular chondrocytes. Refocusing chondrogenic induction optimisation efforts from weeks to the first hours or days of culture, using homogeneous model systems, may benefit efforts to build stable cartilage formed by BMSCs. SignificanceThe macro-pellet model, and assumptions generated using it, have permeated BMSC-based cartilage tissue engineering strategies since the 1990s. Using a micro-pellet model, we show that BMSC chondrogenic kinetics are significantly more rapid than historical macro-pellets data suggests, and that BMSC chondrogenic and hypertrophic commitment is instructed by a single day of TGF-b1 exposure. This highly relevant study demonstrates that: (1) macro-pellets, which are large heterogeneous tissue models confound the differentiation kinetics visible in micro-pellet models;(2) induction strategies should focus on the first hours or days of culture; (3) even a single day of TGF-b1 exposure drives BMSC to form hypertrophic tissue in vivo, requiring early intervention to prevent hypertrophy; and (4) articular chondrocytes and BMSCs respond distinctly to TGF-b1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Micro-pellet culture reveals that bone marrow mesenchymal stromal cell (BMSC) chondrogenic induction is triggered by a single day of TGF-β1 exposure

Futrega

Robey

Crawford

et al. 2019

Preprint

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“…A commercial product CARTISTEM that is manufactured with Hyaluronic acid and allogenic MSCs that is in clinical trials for articular cartilage defects (NCT01733186 and NCT01626677). The most common cell‐based treatment for chondral defects in humans is currently the autologous chondrocyte transplantation, both alone or placed on natural scaffolds . However, that trend might shift if the results of the clinical studies confirm the same potential of biomaterial‐delivered stem cells as the preclinical studies have shown.…”

Section: Applications Of Advanced Biomaterials For Stem Cell Deliverymentioning

confidence: 99%

Advanced Functional Biomaterials for Stem Cell Delivery in Regenerative Engineering and Medicine

Wang

Rivera‐Bolanos

Jiang

et al. 2019

Adv Funct Materials

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Stem cell-based therapies can potentially regenerate many types of tissues and organs, thereby providing solutions to a variety of diseases and injuries. However, acute cell death, uncontrolled differentiation, and low functional engraftment yields remain critical obstacles for clinical translation. Advanced functional biomaterial scaffolds that can deliver stem cells to the targeted tissues/organs and promote stem cell survival, differentiation, and integration to host tissues may potentially transform the clinical outcome of stem cellbased regenerative therapies. In this review, the authors briefly summarize sources of stem cells for transplantation, present the current state of the art in biomaterial design for stem cell delivery, and provide critical analysis for existing materials. Applications to the cardiovascular, neural, and musculoskeletal systems are highlighted with recent nonclinical studies and clinical trials. The authors also discuss how advances in biomaterials research can contribute to regenerative medicine research and stem cell therapies. application in the clinical setting. These challenges include the manipulation of stem cell fate pre-and post-transplantation and protection of the cells during and after their delivery to the target site. [3] The microenvironment, also referred to as stem cell niche, plays key roles in stem cell fate determination. [4] In vivo, the interplay among complex microenvironmental cues precisely regulate stem cell function so they may undergo self-renewal to maintain the stem cell pool or to undergo differentiation to regenerate tissue. However, the majority of current stem cell transplant strategies in clinical trials use injections with a buffer fluid, which provides insufficient protection and manipulation of cell fate. [5] As a result, the vast majority of transplanted cells die during their delivery or within a short time thereafter. Engineering approaches, especially in the biomaterials field, offer strategies to address the challenges and current limitations of stem cell therapy. Innovative design of biomaterials enables delicate control of their biophysical and biochemical properties, which provides an artificial niche to regulate stem cell functions. Delivery of cells via engineered biomaterial carriers can promote cell survival by reducing the microenvironmental shock (shear stress, inflammation, etc.), improving cell retention by preventing cell leakage and enhancing regenerative responses from delivered cells by manipulating stem cell fate. [6] In this review, we summarize and provide perspective on stem cell sources and the state of the art in the design, fabrication, and application of advanced functional biomaterials for stem cell delivery. We discuss current stem cell phenotypes and the requirements in biomaterial design and fabrication for successful stem cell transplantation. We also highlight recent nonclinical and clinical studies of stem cell therapy in the cardiovascular, neural, and musculoskeletal systems. Lastly, we conclude with an outlo...

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“…Furthermore, clinical trials were suggested to assess matrix efficacy and safety. These approaches are of the particular interest especially in reconstructive surgery in case of regeneration of soft tissues damages and wound healing [38,39,40].…”

Section: а B Cmentioning

confidence: 99%

3D culture of murine adipose-derived multipotent mesenchymal stromal cells in hydrogel based on carbomer 974P

Кyryk¹,

Kuchuk²,

Mamchur³

et al. 2018

JCOT

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Actual issues during tissue regeneration are to ensure the survival of transplanted cells at the site of their application and further activity, especially in case of local pathological alterations such as inflammation and ischemia. For this purpose, the matrices that can not only fill the defects of tissues, but also be scaffolds for cells are developed.The aim of this study was to evaluate the effectiveness of 3D cultivation of murine adipose-derived multipotent mesenchymal stromal cells (MSMCs) in hydrogel based on carbomer 974P.Materials and methods. MSMCs were obtained from the adipose tissue of FVB-Cg-Tg(GFPU)5Nagy/J mice transgenic for GFP gene. The cells were phenotyped by flow cytometry and directly differentiated into osteogenic and adipogenic direction to confirm multipotent phenotype. MMSCs were cultured and directly differentiated into osteogenic direction in three-dimensional hydrogel scaffolds. For hydrogel preparation we used carbomer 974P with composition of glycerol, propylene glycol, triethylamine and agarose in original proportion.Results. The three-dimensional hydrogel based on carbomer 974P for the further engraftment with MMSCs was obtained. Modified protocols for the preparation of hydrogels based on carbomer and agarose and their rehydration by culture media for the 3D cultivation of adipose-derived MMSCs have been developed. The optimal concentration of MSMCs and the injection method for engraftment of hydrogels of the required form and size are selected. It was shown that adipose-derived MMSCs in 3D carbomer hydrogel preserve the potential of directed osteogenic differentiation.Conclusion. Three-dimensional hydrogel based on carbomer 974P is capable to support cells, provide the necessary cytoarchitectonics, maintain intercellular interactions, which can promote further long-term survival and specialization of graft.

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Trends in clinical trials for articular cartilage repair by cell therapy

Cited by 84 publications

References 20 publications

Micro-pellet culture reveals that bone marrow mesenchymal stromal cell (BMSC) chondrogenic induction is triggered by a single day of TGF-β1 exposure

Micro-pellet culture reveals that bone marrow mesenchymal stromal cell (BMSC) chondrogenic induction is triggered by a single day of TGF-β1 exposure

Advanced Functional Biomaterials for Stem Cell Delivery in Regenerative Engineering and Medicine

3D culture of murine adipose-derived multipotent mesenchymal stromal cells in hydrogel based on carbomer 974P

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