Hae Lin Jang

Graphene-based materials for tissue engineering ☆

Graphene and its chemical derivatives have been a pivotal new class of nanomaterials and a model system for quantum behavior. The materials excellent electrical conductivity, biocompatibility, surface area and thermal properties are of much interest to the scientific community. Two-dimensional graphene materials have been widely used in various biomedical research areas such as bioelectronics, imaging, drug delivery, and tissue engineering. In this review, we will highlight the recent applications of graphene-based materials in tissue engineering and regenerative medicine. In particular, we will discuss the application of graphene-based materials in cardiac, neural, bone, cartilage, skeletal muscle, and skin/adipose tissue engineering. We will also discuss the potential risk factors of graphene-based materials in tissue engineering. In conclusion, we will outline the opportunities in the usage of graphene-based materials for clinical applications.

Rapid Continuous Multimaterial Extrusion Bioprinting

The development of a multimaterial extrusion bioprinting platform is reported. This platform is capable of depositing multiple coded bioinks in a continuous manner with fast and smooth switching among different reservoirs for rapid fabrication of complex constructs, through digitally controlled extrusion of bioinks from a single printhead consisting of bundled capillaries synergized with programmed movement of the motorized stage.

Development of hydrogels for regenerative engineering

The aim of regenerative engineering is to restore complex tissues and biological systems through convergence in the fields of advanced biomaterials, stem cell science, and developmental biology. Hydrogels are one of the most attractive biomaterials for regenerative engineering, since they can be engineered into tissue mimetic 3D scaffolds to support cell growth due to their similarity to native extracellular matrix. Advanced nano‐ and micro‐technologies have dramatically increased the ability to control properties and functionalities of hydrogel materials by facilitating biomimetic fabrication of more sophisticated compositions and architectures, thus extending our understanding of cell‐matrix interactions at the nanoscale. With this perspective, this review discusses the most commonly used hydrogel materials and their fabrication strategies for regenerative engineering. We highlight the physical, chemical, and functional modulation of hydrogels to design and engineer biomimetic tissues based on recent achievements in nano‐ and micro‐technologies. In addition, current hydrogel‐based regenerative engineering strategies for treating multiple tissues, such as musculoskeletal, nervous and cardiac tissue, are also covered in this review. The interaction of multiple disciplines including materials science, cell biology, and chemistry, will further play an important role in the design of functional hydrogels for the regeneration of complex tissues.

Development of nanomaterials for bone-targeted drug delivery

Bone is one of the major organs of the human body; it supports and protects other organs, produces blood cells, stores minerals, and regulates hormones. Therefore, disorders in bone can cause serious morbidity, complications, or mortality of patients. However, despite the significant occurrence of bone diseases, such as osteoarthritis (OA), osteoporosis (OP), non-union bone defects, bone cancer, and myeloma-related bone disease, their effective treatments remain a challenge. In this review, we highlight recent progress in the development of nanotechnology-based drug delivery for bone treatment, based on its improved delivery efficiency and safety. We summarize the most commonly used nanomaterials for bone drug delivery. We then discuss the targeting strategies of these nanomaterials to the diseased sites of bone tissue. We also highlight nanotechnology-based drug delivery to bone cells and subcellular organelles. We envision that nanotechnology-based drug delivery will serve as a powerful tool for developing treatments for currently incurable bone diseases.

Engineering vascularized and innervated bone biomaterials for improved skeletal tissue regeneration

Blood vessels and nerve fibers are distributed throughout the entirety of skeletal tissue, and play important roles during bone development and fracture healing by supplying oxygen, nutrients, and cells. However, despite the successful development of bone mimetic materials that can replace damaged bone from a structural point of view, most of the available bone biomaterials often do not induce sufficient formation of blood vessels and nerves. In part, this is due to the difficulty of integrating and regulating multiple tissue types within artificial materials, which causes a gap between native skeletal tissue. Therefore, understanding the anatomy and underlying interaction mechanisms of blood vessels and nerve fibers in skeletal tissue is important to develop biomaterials that can recapitulate its complex microenvironment. In this perspective, we highlight the structure and osteogenic functions of the vascular and nervous system in bone, in a coupled manner. In addition, we discuss important design criteria for engineering vascularized, innervated, and neurovascularized bone implant materials, as well as recent advances in the development of such biomaterials. We expect that bone implant materials with neurovascularized networks can more accurately mimic native skeletal tissue and improve the regeneration of bone tissue.

Synergistic interplay between the two major bone minerals, hydroxyapatite and whitlockite nanoparticles, for osteogenic differentiation of mesenchymal stem cells

The inorganic part of human bone is mainly composed of hydroxyapatite (HAP: Ca10(PO4)6(OH)2) and whitlockite (WH: Ca18Mg2(HPO4)2(PO4)12) minerals, where the WH phase occupies up to 20-35% of total weight. These two bone minerals have different crystal structures and physicochemical properties, implying their distinguished role in bone physiology. However, until now, the biological significance of the presence of a certain ratio between HAP and WH in bone is unclear. To address this fundamental question, bone mimetic scaffolds are designed to encapsulate human mesenchymal stem cells (MSCs) for assessing their osteogenic activity depending on different ratios of HAP and WH. Interestingly, cellular growth and osteogenic differentiation are significantly promoted when MSCs are grown with a 3-1 ratio of HAP and WH nanoparticles, which is similar to bone. One of the reasons for this synergism between HAP and WH in hydrogel scaffolds is that, while WH nanoparticles can enhance osteogenic differentiation of MSCs compared to HAP, WH counterintuitively decreases the mechanical stiffness of nanocomposite hydrogels and hinders the osteogenic activity of cells. Taken together, these findings identify the optimal ratio between two major minerals in bone mimetic scaffolds to maximize the osteogenic differentiation of MSCs. STATEMENT OF SIGNIFICANCE Human bone minerals are composed of HAP and WH inorganic nanoparticles which have different material properties. However, the reason for the coexistence of HAP and WH in human bone is not fully identified, and HAP and WH composite biomaterial has not been utilized in the clinic. In this study, we have developed bone mimetic HAP and WH nanocomposite hydrogel scaffolds with various ratios. Importantly, we found out that HAP can promote the mechanical stiffness of the composite hydrogel scaffolds while WH can enhance the osteogenic activity of stem cells, which together induced synergism to maximize osteogenic differentiation of stem cells when mixed into 3-1 ratio that is similar to human bone.

3D Printed Anchoring Sutures for Permanent Shaping of Tissues

Sutures are one of the most widely used devices for adhering separated tissues after injury or surgery. However, most sutures require knotting, which can create a risk of inflammation, and can act as mechanically weak points that often result in breakage and slipping. Here, an anchoring suture is presented with a design that facilitates its propagation parallel to the suturing direction, while maximizing its resistive force against the opposite direction of external force to lock its position in tissues. Different microstructures of suture anchors are systematically designed using orthogonal arrays, and selected based on shape factors associated with mechanical strength. 3D printing is used to fabricate different types of hollow microstructured suture anchors, and optimize their structure for the effective shaping of tissues. To define the structural design for fixing tissues, the maximum force required to pull 3D printed anchors in different directions is examined with tissues. The tissue reshaping function of suture anchors is further simulated ex vivo by using swine ear, nose, and skin, and bovine muscle tendon. This study provides advantages for building functional sutures that can be used for permanently reshaping tissues with enhanced mechanical strength, eliminating the need for knotting to improve surgical efficiency.