Chondral and osteochondral lesions due to injury or other pathology commonly result in the development of osteoarthritis, eventually leading to progressive total joint destruction. Although current progress suggests that biologic agents can delay the advancement of deterioration, such drugs are incapable of promoting tissue restoration. The limited ability of articular cartilage to regenerate renders joint arthroplasty an unavoidable surgical intervention. This Review describes current, widely used clinical repair techniques for resurfacing articular cartilage defects; short-term and long-term clinical outcomes of these techniques are discussed. Also reviewed is a developmental pipeline of acellular and cellular regenerative products and techniques that could revolutionize joint care over the next decade by promoting the development of functional articular cartilage. Acellular products typically consist of collagen or hyaluronic-acid-based materials, whereas cellular techniques use either primary cells or stem cells, with or without scaffolds. Central to these efforts is the prominent role that tissue engineering has in translating biological technology into clinical products; therefore, concomitant regulatory processes are also discussed.

https://escholarship.org/content/qt76m4g3q5/qt76m4g3q5.pdf?t=oe66jy

Repair and tissue engineering techniques for articular cartilage

Articular cartilage was predicted to be one of the first tissues to successfully be regenerated, but this proved incorrect In contrast, bone (but also vasculature and cardiac tissues) has seen numerous successful reparative approaches, despite consisting of multiple cell and tissue types and, thus, possessing more complex design requirements Here, we use bone-regeneration successes to highlight cartilage-regeneration challenges: such as selecting appropriate cell sources and scaffolds, creating biomechanically suitable tissues, and integrating to native tissue We also discuss technologies that can address the hurdles of engineering a tissue possessing mechanical properties that are unmatched in human-made materials and functioning in environments unfavorable to neotissue growth

/pdf/unlike-bone-cartilage-regeneration-remains-elusive-1v15bd07dw.pdf

Unlike Bone, Cartilage Regeneration Remains Elusive

Mesenchymal stem cells (MSCs) are known to have a potential for articular cartilage regeneration. However, most studies focused on focal cartilage defect through surgical implantation. For the treatment of generalized cartilage loss in osteoarthritis, an alternative delivery strategy would be more appropriate. The purpose of this study was to assess the safety and efficacy of intra-articular injection of autologous adipose tissue derived MSCs (AD-MSCs) for knee osteoarthritis. We enrolled 18 patients with osteoarthritis of the knee and injected AD MSCs into the knee. The phase I study consists of three dose-escalation cohorts; the low-dose (1.0 × 10(7) cells), mid-dose (5.0 × 10(7)), and high-dose (1.0 × 10(8)) group with three patients each. The phase II included nine patients receiving the high-dose. The primary outcomes were the safety and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) at 6 months. Secondary outcomes included clinical, radiological, arthroscopic, and histological evaluations. There was no treatment-related adverse event. The WOMAC score improved at 6 months after injection in the high-dose group. The size of cartilage defect decreased while the volume of cartilage increased in the medial femoral and tibial condyles of the high-dose group. Arthroscopy showed that the size of cartilage defect decreased in the medial femoral and medial tibial condyles of the high-dose group. Histology demonstrated thick, hyaline-like cartilage regeneration. These results showed that intra-articular injection of 1.0 × 10(8) AD MSCs into the osteoarthritic knee improved function and pain of the knee joint without causing adverse events, and reduced cartilage defects by regeneration of hyaline-like articular cartilage.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/stem.1634

Intra‐Articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the Knee: A Proof‐of‐Concept Clinical Trial

The current need for organ and tissue replacement, repair, and regeneration for patients is continually growing such that supply is not meeting demand primarily due to a paucity of donors as well as biocompatibility issues leading to immune rejection of the transplant. In order to overcome these drawbacks, scientists have investigated the use of scaffolds as an alternative to transplantation. These scaffolds are designed to mimic the extracellular matrix (ECM) by providing structural support as well as promoting attachment, proliferation, and differentiation with the ultimate goal of yielding functional tissues or organs. Initial attempts at developing scaffolds were problematic and subsequently inspired an interest in 3D printing as a mode for generating scaffolds. Utilizing three-dimensional printing (3DP) technologies, ECM-like scaffolds can be produced with a high degree of complexity, where fine details can be included at a micrometer level. In this Review, the criteria for printing viable and functional scaffolds, scaffolding materials, and 3DP technologies used to print scaffolds for tissue engineering are discussed. Creating biofunctional scaffolds could potentially help to meet the demand by patients for tissues and organs without having to wait or rely on donors for transplantation.

3D Printing of Scaffolds for Tissue Regeneration Applications

Progress in 3D bioprinting technology for tissue/organ regenerative engineering

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)60668-X.pdf

Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study

Cell transplantation has been well explored for cartilage regeneration. We recently showed that the entire articular surface of a synovial joint can regenerate by endogenous cell homing and without cell transplantation. However, the sources of endogenous cells that regenerate articular cartilage remain elusive. Here, we studied whether cytokines not only chemotactically recruit adipose stem cells (ASCs), mesenchymal stem cells (MSCs), and synovium stem cells (SSCs) but also induce chondrogenesis of the recruited cells. Recombinant human transforming growth factor-β3 (TGF-β3; 100 ng) and/or recombinant human stromal derived factor-1β (SDF-1β; 100 ng) was control released into an acellular collagen sponge cube with underlying ASCs, MSCs, or SSCs in monolayer culture. Although all cell types randomly migrated into the acellular collagen sponge cube, TGF-β3 and/or SDF-1β recruited significantly more cells than the cytokine-free control group. In 6 wk, TGF-β3 alone recruited substantial numbers of ASCs (558±65) and MSCs (302±52), whereas codelivery of TGF-β3 and SDF-1β was particularly chemotactic to SSCs (400±120). Proliferation of the recruited cells accounted for some, but far from all, of the observed cellularity. TGF-β3 and SDF-1β codelivery induced significantly higher aggrecan gene expression than the cytokine-free group for ASCs, MSCs, and SSCs. Type II collagen gene expression was also significantly higher for ASCs and SSCs by SDF-1 and TGF-β3 codelivery. Remarkably, the expression of aggrecan and type II collagen was detected among all cell types. Thus, homing of multiple stem/progenitor cell populations may potentially serve as an alternative or adjunctive approach to cell transplantation for cartilage regeneration.

Chondrogenesis by chemotactic homing of synovium, bone marrow, and adipose stem cells in vitro

From its inception, tissue engineering has had three tenets: cells, biomaterial scaffolds and signaling molecules. Among the triad, cells are the center piece, because cells are the building blocks of tissues. For decades, cell therapies have focused on the procurement, manipulation and delivery of healthy cells for the treatment of diseases or trauma. Given the complexity and potential high cost of cell delivery, there is recent and surging interest to orchestrate endogenous cells for tissue regeneration. Biomaterial scaffolds are vital for many but not all, tissue-engineering applications and serve to accommodate or promote multiple cellular functions. Signaling molecules can be produced by transplanted cells or endogenous cells, or delivered specifically to regulate cell functions. This review highlights recent work in tissue engineering and cell therapies, with a focus on harnessing the capacity of endogenous cells as an alternative or adjunctive approach for tissue regeneration.

Musculoskeletal tissue engineering by endogenous stem/progenitor cells.

Current augmentative and reconstructive rhinoplasty surgeries utilize autologous tissue grafts or synthetic bioinert materials to repair nasal trauma or attain an aesthetic shape. Autologous grafts are associated with donor site trauma and morbidity. Synthetic materials are widely used but often yield an unnatural appearance and are prone to infection or dislocation. There is an acute clinical need for the generation of native tissues to serve as rhinoplasty grafts without the undesirable features that are associated with autologous grafts or current synthetic materials. Here, we developed a bioactive scaffold that not only recruited cells in the nasal dorsum in vivo, but also induced chondrogenesis of the recruited cells. Bilayered scaffolds were fabricated with alginate containing gelatin microspheres encapsulating cytokines atop a porous poly (lactic-co-glycolic acid) (PLGA) base. Gelatin microspheres were fabricated to contain recombinant human TGFβ3 at doses of 200, 500 or 1000 ng with PBS-loaded microspheres as a control. We first created a rat model of augmentation rhinoplasty by implanting bilayered scaffolds atop the native nasal cartilage surface that was scored to induce cell migration. Tissue formation and chondrogenesis in PLGA scaffolds were evaluated by image analysis and histological staining with Hematoxylin and Eosin, Toluidine Blue, Verhoeff Elastic-Van Geison, and aggrecan immunohistochemistry. Sustained release of increasing doses of TGFβ3 for up to the tested 10 wks promoted orthotopic cartilage-like tissue formation in a dose dependent manner. These findings represent the first attempt to engineer cartilage tissue by cell homing for rhinoplasty, and combine the advantage of autologous tissue formation by cytotactic factors embedded in a biomaterial scaffold that could potentially serve as an alternative material for augmentative and reconstructive rhinoplasty.

/pdf/engineered-nasal-cartilage-by-cell-homing-a-model-for-31z4vv9bco.pdf

Engineered nasal cartilage by cell homing: a model for augmentative and reconstructive rhinoplasty

A multitude of cytotactic cues direct cell migration in development, cancer metastasis and wound healing. However, our understanding of cell motility remains fragmented partially because current migration devices only allow the study of independent factors. We developed a cell motility assay that allows competitive recruitment of a given cell population simultaneously by gradients of multiple cytotactic cues, observable under real-time imaging. Well-defined uniform gradients of cytotactic cues can be independently generated and sustained in each channel. As a case study, bone marrow mesenchymal stem/stromal cells (MSCs) were exposed to 15 cytokines that are commonly present in arthritis. Cytokines that induced robust recruitment of MSCs in multiple groups were selected to ‘compete’ in a final round to yield the most chemotactic factor(s) based on cell migration numbers, distances, migration indices and motility over time. The potency of a given cytokine in competition frequently differed from its individual action, substantiating the need to test multiple cytokines concurrently due to synergistic or antagonistic effects. This new device has the rare capacity to screen molecules that induce cell migration in cancer therapy, drug development and tissue regeneration.

/pdf/competitive-stem-cell-recruitment-by-multiple-cytotactic-3o41d9w1ds.pdf

Avital Mendelson

Papers

Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study

Chondrogenesis by chemotactic homing of synovium, bone marrow, and adipose stem cells in vitro

Musculoskeletal tissue engineering by endogenous stem/progenitor cells.

Engineered nasal cartilage by cell homing: a model for augmentative and reconstructive rhinoplasty

Competitive Stem Cell Recruitment by Multiple Cytotactic Cues