Nasal chondrocytes (NC) are present in the hyaline cartilage of the nasal septum and in fact are the only cell type within the tissue. Similar to chondrocytes present in articular cartilage, NC express extracellular matrix proteins such as glycosaminoglycans and collagen. [1]
At birth the nasal septum, except for the vomer ‘’anlage” is completely cartilaginous. In the second half of the first year of life, the septum progressively ossifies in posterior-anterior direction by a process of endochondral ossification. [2] The remaining cartilaginous part (characterized as hyaline cartilage) of the human nasal septum has a specific three-dimensional organization with regards to local differences in cell size and the amounts of extracellular matrix. In the outer region of the cartilage, NC are numerous, small, flat and oriented parallel to the surface. In the intermediate and central regions, NC are spheroid in shape, less dense, and are aligned perpendicular to the cartilage surface. [3] The cartilage matrix is mainly composed of type II collagen (90-95%), although small amounts of type IX and XI collagen are also found. [4] Nasal cartilage is tightly connected to perichondrium, consisting of several layers of connective tissue fibers (mainly based on type I collagen) running parallel to the cartilage. [5]
Articular chondrocytes have typically been the cell type used for cartilage tissue engineering strategies for articular cartilage repair. Since NC can also express hyaline cartilage specific extracellular matrix proteins such as glycosaminoglycans and collagen, NC have recently also been used for the in vitro engineering of cartilage tissues.
Harvesting of nasal cartilage is minimally invasive, can be performed in an outpatient procedure under local anesthesia and is associated with minimal morbidity. [6] NC can be isolated from nasal septal cartilage biopsies by enzymatic digestion using collagenase type I, II or IV (at different combination and concentration – varying from 0.15% to 0.6% –) alone or after an initial short pre-incubation phase with pronase (0.2% - 1%). [7] [8] [9] [10] [11] [12] Cell yield after enzymatic digestion of the nasal cartilage was estimated to be 2,100 - 3,700 cells/mg of tissue. [7] [12] Alternatively, NC can be isolated by outgrowth culture of nasal cartilage fragments. [8]
After isolation from septal cartilage biopsies, NC can be extensively expanded in numbers by conventional in vitro cell culture methods (monolayer culture in flasks or Petri dishes). The proliferation rate of NC was reported to be increased in the presence of specific growth factors such as TGF-beta and FGF-2 [12] [13] or culture supplements like Insulin-Transferrin-Selenium. [7] NC cultured in medium containing autologous serum exhibit similar proliferation rates to NC cultured with medium supplemented with fetal bovine serum. [13] Although articular chondrocytes derived from older individuals have been shown to have a lower proliferation capacity than from younger donors, NC have been shown to have significantly less age-dependence. [13] [14]
Similar to other chondrocytes from hyaline cartilage tissues in other locations in the human body, NC undergo a process of cell de-differentiation during monolayer culture. NC de-differentiation can be characterized by a gradual acquisition of a fibroblastic morphology, the expression of proteins associated with an undifferentiated mesenchymal cell phenotype (e.g., type I collagen and versican), and decreased expression of hyaline cartilage proteins (e.g., type II collagen and aggrecan). [9] However, NC can re-differentiate when transferred back into a more physiological three-dimensional environment. Abundant production of cartilage specific matrix has been reported by expanded NC when induced to re-differentiate in micromass pellets, [11] [12] [14] [15] alginate beads, [16] [17] [18] [19] [20] hydrogels, [7] [21] or into porous scaffolds based on polyglycolic acid, [9] [19] [22] polyethylene glycol terephthalate/polybuthylene terephalate, [23] collagen, [24] or hyaluronic acid. [1] [14] [25] Supplementation with specific growth factors (e.g., TGF-beta, IGF-1, and GDF-5) during re-differentiation has been shown to enhance the accumulation of glycosaminoglycans (GAG) and type II collagen as well as the biomechanical properties of the generated constructs. [20] [26]
Autologous serum has also been used during NC re-differentiation in place of fetal bovine serum with similar efficacy. [14] [26] [27] Studies that directly compared the re-differentiation of articular chondrocytes to NC have shown that the cartilage forming capacity of NC was higher and more reproducible than that of articular chondrocytes [24] [25] [28] with lower donor-related dependency. [13] [14] Additionally NC have been recently shown to exhibit features of self-renewal capability, being able to form cartilage tissue following serial cloning possibly due to their neuro-ectodermal origin. [29]
Pre-clinical investigations have been undertaken using various animal models to provide proof-of-principle of the clinical potential of NC-based tissue engineered constructs for cartilage reconstruction. The maturation of human NC engineered grafts has often been assessed in the subcutaneous pocket of nude mice, i.e., an environment highly vascularized and permissive to, but not inductive of, chondrogenesis. [30] [31] The extent of cartilage matrix production and the mechanical properties of NC-based constructs have been reported to increase in such ectopic in vivo models. [21] [13] [18] [22] [32] [33] [34] An ectopic mouse model was also used in order to test the effects of different production methods for generating large clinically relevant-sized NC-based tissue grafts. [26]
Although these models can yield insightful results, nude mice are not capable of eliciting a significant immune response, and therefore these studies cannot predict the prognosis of implanted engineered septal cartilage in an immunocompetent host. As an alternative, an orthotopic rat model has been established to study nasal septum repair. In this model, septal cartilage was first perforated to create a defect, and subsequently, an engineered cartilage graft implanted into the defect during the same surgical procedure [35]
Using an orthotopic large animal model to study repair of articular cartilage defects, engineered NC-based cartilage grafts were implanted into the condyle of goats. In this study, it was determined that NC directly contributed to the repair of the articular cartilage defects and resulted in a superior outcome as compared to engineered articular chondrocyte-based grafts. [36]
Engineered cartilage tissue, based on autologous NC, has recently been used by plastic surgeons for the reconstruction of nasal cartilage defects. Tissue engineered cartilage grafts based on NC as autologous grafts for the reconstruction of the alar lobule of the nose after skin tumor resection in a first-in-man clinical trial (ClinicalTrials.gov, number NCT01242618) [29] (see figure on the right). Their results demonstrated that the engineered grafts could lead to complete structural, functional and aesthetic satisfaction. Moreover, since harvesting of the nasal cartilage biopsy was minimally invasive, it could be performed in an outpatient procedure under local anesthesia, and was therefore associated with minimal morbidity. [6]
Several studies have demonstrated that NC are compatible with the environmental features typical of the injured knee (e.g., in terms of response to inflammatory molecules, mechanical loading and genetic molecular signature). [24] [25] [30] Thus nasal chondrocytes have been proposed as an alternative cell source for the repair of articular cartilage defects. A phase I clinical trial (ClinicalTrials.gov, number NCT 01605201) was conducted to test the safety and feasibility of implanting a tissue engineered cartilage graft based on autologous nasal chondrocytes for the regeneration of knee cartilage defects. The clinical observations of the first 10 patients of this study indicated not only safety and feasibility of the procedure, but together with Magnetic Resonance Imaging (MRI) and delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) data, also showed promising results for efficacy of the treatment as indicated by significant improvement in clinical scores and regeneration of hyaline repair tissue after 24 months. [37] Based on this study, a multi-center phase II clinical trial was initiated and is currently ongoing to assess the efficacy of the NC-based cartilage grafts for the repair of traumatic knee cartilage defects (BIO-CHIP; funded by the European Union through the Horizon 2020 program, grant number 681103).
Cartilage is a resilient and smooth type of connective tissue. It is a semi-transparent and non-porous type of tissue. It is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck and the bronchial tubes, and the intervertebral discs. In other taxa, such as chondrichthyans, but also in cyclostomes, it may constitute a much greater proportion of the skeleton. It is not as hard and rigid as bone, but it is much stiffer and much less flexible than muscle. The matrix of cartilage is made up of glycosaminoglycans, proteoglycans, collagen fibers and, sometimes, elastin. It usually grows quicker than bone.
Rhinoplasty, commonly called nose job, medically called nasal reconstruction, is a plastic surgery procedure for altering and reconstructing the nose. There are two types of plastic surgery used – reconstructive surgery that restores the form and functions of the nose and cosmetic surgery that changes the appearance of the nose. Reconstructive surgery seeks to resolve nasal injuries caused by various traumas including blunt, and penetrating trauma and trauma caused by blast injury. Reconstructive surgery can also treat birth defects, breathing problems, and failed primary rhinoplasties. Rhinoplasty may remove a bump, narrow nostril width, change the angle between the nose and the mouth, or address injuries, birth defects, or other problems that affect breathing, such as a deviated nasal septum or a sinus condition. Surgery only on the septum is called a septoplasty.
Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biological tissues. Tissue engineering often involves the use of cells placed on tissue scaffolds in the formation of new viable tissue for a medical purpose, but is not limited to applications involving cells and tissue scaffolds. While it was once categorized as a sub-field of biomaterials, having grown in scope and importance, it can is considered as a field of its own.
The nasal septum separates the left and right airways of the nasal cavity, dividing the two nostrils.
Hyaline cartilage is the glass-like (hyaline) and translucent cartilage found on many joint surfaces. It is also most commonly found in the ribs, nose, larynx, and trachea. Hyaline cartilage is pearl-gray in color, with a firm consistency and has a considerable amount of collagen. It contains no nerves or blood vessels, and its structure is relatively simple.
Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word chondroblast is commonly used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.
In cellular biology, mechanotransduction is any of various mechanisms by which cells convert mechanical stimulus into electrochemical activity. This form of sensory transduction is responsible for a number of senses and physiological processes in the body, including proprioception, touch, balance, and hearing. The basic mechanism of mechanotransduction involves converting mechanical signals into electrical or chemical signals.
Chondroblasts, or perichondrial cells, is the name given to mesenchymal progenitor cells in situ which, from endochondral ossification, will form chondrocytes in the growing cartilage matrix. Another name for them is subchondral cortico-spongious progenitors. They have euchromatic nuclei and stain by basic dyes.
Chondrogenesis is the biological process through which cartilage tissue is formed and developed. This intricate and tightly regulated cellular differentiation pathway plays a crucial role in skeletal development, as cartilage serves as a fundamental component of the embryonic skeleton. The term "chondrogenesis" is derived from the Greek words "chondros," meaning cartilage, and "genesis," meaning origin or formation.
Articular cartilage, most notably that which is found in the knee joint, is generally characterized by very low friction, high wear resistance, and poor regenerative qualities. It is responsible for much of the compressive resistance and load bearing qualities of the knee joint and, without it, walking is painful to impossible. Osteoarthritis is a common condition of cartilage failure that can lead to limited range of motion, bone damage and invariably, pain. Due to a combination of acute stress and chronic fatigue, osteoarthritis directly manifests itself in a wearing away of the articular surface and, in extreme cases, bone can be exposed in the joint. Some additional examples of cartilage failure mechanisms include cellular matrix linkage rupture, chondrocyte protein synthesis inhibition, and chondrocyte apoptosis. There are several different repair options available for cartilage damage or failure.
The nasal cartilages are structures within the nose that provide form and support to the nasal cavity. The nasal cartilages are made up of a flexible material called hyaline cartilage in the distal portion of the nose. There are five individual cartilages that make up the nasal cavity: septal nasal cartilage, lateral nasal cartilage, major alar cartilage, minor alar cartilage, and vomeronasal cartilage.
Articular cartilage repair treatment involves the repair of the surface of the articular joint's hyaline cartilage, though these solutions do not perfectly restore the articular cartilage. These treatments have been shown to have positive results for patients who have articular cartilage damage. They can provide some measure of pain relief, while slowing down the accumulation of damage, or delaying the need for joint replacement surgery.
Autologous chondrocyte implantation is a biomedical treatment that repairs damages in articular cartilage. ACI provides pain relief while at the same time slowing down the progression or considerably delaying partial or total joint replacement surgery.
Mesenchymal stem cells (MSCs) are multipotent cells found in multiple human adult tissues, including bone marrow, synovial tissues, and adipose tissues. Since they are derived from the mesoderm, they have been shown to differentiate into bone, cartilage, muscle, and adipose tissue. MSCs from embryonic sources have shown promise scientifically while creating significant controversy. As a result, many researchers have focused on adult stem cells, or stem cells isolated from adult humans that can be transplanted into damaged tissue.
A fibrin scaffold is a network of protein that holds together and supports a variety of living tissues. It is produced naturally by the body after injury, but also can be engineered as a tissue substitute to speed healing. The scaffold consists of naturally occurring biomaterials composed of a cross-linked fibrin network and has a broad use in biomedical applications.
Autologous matrix-induced chondrogenesis (AMIC) is a treatment for articular cartilage damage. It combines microfracture surgery with the application of a bi-layer collagen I/III membrane. There is tentative short to medium term benefits as of 2017.
Cartilage repair techniques are the current focus of large amounts of research. Many different strategies have been proposed as solutions for cartilage defects. Surgical techniques currently being studied include:
Gene therapy for osteoarthritis is the application of gene therapy to treat osteoarthritis (OA). Unlike pharmacological treatments which are administered locally or systemically as a series of interventions, gene therapy aims to establish sustained therapeutic effect after a single, local injection.
The in vivo bioreactor is a tissue engineering paradigm that uses bioreactor methodology to grow neotissue in vivo that augments or replaces malfunctioning native tissue. Tissue engineering principles are used to construct a confined, artificial bioreactor space in vivo that hosts a tissue scaffold and key biomolecules necessary for neotissue growth. Said space often requires inoculation with pluripotent or specific stem cells to encourage initial growth, and access to a blood source. A blood source allows for recruitment of stem cells from the body alongside nutrient delivery for continual growth. This delivery of cells and nutrients to the bioreactor eventually results in the formation of a neotissue product.
Artificial cartilage is a synthetic material made of hydrogels or polymers that aims to mimic the functional properties of natural cartilage in the human body. Tissue engineering principles are used in order to create a non-degradable and biocompatible material that can replace cartilage. While creating a useful synthetic cartilage material, certain challenges need to be overcome. First, cartilage is an avascular structure in the body and therefore does not repair itself. This creates issues in regeneration of the tissue. Synthetic cartilage also needs to be stably attached to its underlying surface i.e. the bone. Lastly, in the case of creating synthetic cartilage to be used in joint spaces, high mechanical strength under compression needs to be an intrinsic property of the material.
