Biomaterials and tissue engineering approaches using glycosaminoglycans for tissue repair: Lessons learned from the native extracellular matrix

Abstract

Glycosaminoglycans (GAGs) are an important component of the extracellular matrix as they influence cell behavior and have been sought for tissue regeneration, biomaterials, and drug delivery applications. GAGs are known to interact with growth factors and other bioactive molecules and impact tissue mechanics. This review provides an overview of native GAGs, their structure, and properties, specifically their interaction with proteins, their effect on cell behavior, and their mechanical role in the ECM. GAGs' function in the extracellular environment is still being understood however, promising studies have led to the development of medical devices and therapies. Native GAGs, including hyaluronic acid, chondroitin sulfate, and heparin, have been widely explored in tissue engineering and biomaterial approaches for tissue repair or replacement. This review focuses on orthopaedic and wound healing applications. The use of GAGs in these applications have had significant advances leading to clinical use. Promising studies using GAG mimetics and future directions are also discussed. STATEMENT OF SIGNIFICANCE: Glycosaminoglycans (GAGs) are an important component of the native extracellular matrix and have shown promise in medical devices and therapies. This review emphasizes the structure and properties of native GAGs, their role in the ECM providing biochemical and mechanical cues that influence cell behavior, and their use in tissue regeneration and biomaterial approaches for orthopaedic and wound healing applications.

Keywords: Biomaterials; Extracellular Matrix; Glycosaminoglycans; Scaffolds; Tissue Engineering.

Fig. 1.

Structure of natural glycosaminoglycans.

Fig. 2.

Schematic diagram of the presentation of BMP-2 on calcium phosphate cement (CPC) and calcium phosphate cement-polydopamine-chondroitin sulfate (CPC-PDA-CS) scaffolds and the interaction of BMPRs on MSCs. A) Burst release is observed on the scaffolds without CS, resulting in low expression of BMPRs, thus decreased SMAD 1/5/8 and ERK1/2 signaling. B) Inclusion of CS to scaffolds localizes BMP-2 to the scaffolds, resulting in high expression of BMPRs and high SMAD 1/5/8 and ERK1/2 signaling. Reproduced with permission [3].

Fig. 3.

(A) Immunohistology of osteopontin-positive cells (osteoblasts and preosteoblasts) in the screw threads of the external fixation pins. More osteoblasts were seen around the Ti/Coll and Ti/Coll/CS-implants (arrows). (B) average number of osteopontin-positive and (C) TRAP-positive cells (osteoclasts) per screw thread around the external fixation pins. The number of osteoblasts increased significantly around the Ti/Coll and Ti/Coll/CS implants compared to Ti (*p < 0.05). The number of osteoclasts was significantly lower around Ti/Coll/CS compared to all other implants (*p < 0.001). Reproduced with permission [1].

Fig. 4.

(A) SEM-Images of the fiber reinforced hydroxyapatite (HAp)/Col and HAp/Col/CS composites. Original magnification 10,000 X [2]. (B) CT scans of HAp/Col and HAp/Col/CS implants after 3 months showing a considerable bone formation (arrows) around HAp/Col/CS implants. (C-D) Morphological changes in the bone/implant interface around HAp/Col and HAp/Col/CS implants after 3 months. (C) H&E staining, a–b, 2X magnification, c–d, 200X magnification. Newly formed woven bone is seen around HAp/Col/CS implant surface (arrows). Remaining fibrous and granulation tissue in the interface around HAp/Col implants is visible. (D) Immunostaining, (a,b) Osteonectin stain showing newly formed vessels around HA/Col/CS implants (arrow), absent in HAp/Col implants. 200X magnification (c) Osteopontin positive osteoblasts visible near HAp/Col/CS implant (arrows) (d) TRAP positive osteoclasts around HAp/Col implant (*) c-d, 400X magnification. Reproduced with permission [9].

Fig. 5.

(A) Preparation of CS hydrogels in the presence of transduced MSCs. (B) Measurement of colocalization for calcein and RFP. (C) Cumulative release of BMP-2 over 15 days from CS gels only and CS gels with 1 million BMP-2 MSCs. (D) Percentage of the total amount released from CS gels loaded with BMP-2 MSCs, CS with rhBMP2, and collagen sponges with rhBMP2. Reproduced with permission [4].

Fig. 6.

(A) Magnetic resonance imaging of a grade 4 chondral lesion involving articular surface of medial femoral condyle in 50-year-old male(a). 1-year follow-up MRI showing complete filling of the defect (b). 5-year follow-up MRI showing establishment of smooth articular surface (c) (B) Biopsy report at 2-year follow up shows Safranin O staining shows hyaline-like tissue, intensely stained for proteoglycans, slightly hypercellular and with some fibrous features. The superficial layer is regular, the surface is smooth and the cells are homogeneously distributed. The subchondral bone is normal and normal passage bone/cartilage(a). Collagen type I immunostaining showing no collagen type I positive matrix (b). Collagen Type II immunostaining showing presence of type II collagen within the matrix (c) Reproduced with permission [5]

Fig. 7.

Hydrogel was implanted in chondral defects of a rabbit (A-B) and goat condyle (C-E) with or without the CS adhesive. (A) MRI of the articular defects treated with the CS adhesive and hydrogel (+ CS) demonstrated an MRI signal and T₂ signal change, whereas defects that were not treated with CS adhesive before hydrogel placement (−CS) were empty after 5 weeks. (B) Safranin-O staining of defects in the rabbit treated with CS adhesive with hydrogel revealed enhanced proteoglycan deposition and tissue development. (C) Empty control defects after 6 months & defects treated with the gel and adhesive. (D) Histomorphometric analysis quantified the area of tissue fill and positive Safranin-O staining and demonstrated statistically significant differences between the control and treated chondral defects (E) Histological analysis confirmed that the gross pictures with the empty defect contained minimal tissue fill compared with the treated defect. Most of the tissue fill in the treated defects stained for Safranin-O, and the O’Driscoll (OD) score of the treated defects was greater than that of the controls (17.7 versus 14.8). The scale bars represents 1 mm. Reproduced with permission [8].