Bone injuries and defects caused by complex breaks and pathological fractures arising from malformation, osteoporosis, and tumors pose a significant clinical challenge for treatment and account for 60% to 67% of all unintentional injuries in the United States per annum.^1,2 It has been reported that more than 34 million musculoskeletal-related surgeries are performed each year in the United States.³ Clinically, the main options available for the surgical treatment of musculoskeletal injuries include transplantation of autografts/allografts and utilization of synthetic substitutes composed of metals, ceramics, and/or polymers.¹ Surgical procedures to align and stabilize with metallic pins, screws, plates, and rods involve multiple procedures with associated risk of donor site morbidity.¹ Moreover, synthetic metal substitutes merely replace damaged tissues or organs rather than serve as a platform for repair and regeneration of tissue defects.² To overcome the drawbacks of current methods, regenerative engineering approaches provide an alternative for translational treatment. Regenerative engineering is an approach converging advanced materials science, stem cell science, physics, developmental biology, and clinical translation. Regenerative engineering will harness and expand these newly developed tools toward the regeneration of complex tissues.^4,5

Native extracellular matrix (ECM) is majorly composed of nanoscale collagen fibers that offer structural integrity to tissues.^6,7 In bone, the basic building block of the ECM is the mineralized collagen I fibrils.¹ In addition to the nanofibrous architecture, high porosity is needed to allow for cell ingrowth and efficient mass transport of nutrients, oxygen, growth factors, and waste products to promote vascularization and avoid necrosis. Advanced biomaterial scaffolds are designed and developed through regenerative engineering techniques to mimic both the structure and function of the native ECM.⁸ Different biomaterial cues are incorporated into scaffolds to promote cell-matrix interactions for desirable tissue regeneration (Figure 1).

Among the various processing techniques used in the recent years for the fabrication of nanofibrous scaffolds, the electrospinning process is the most promising and versatile technique.³ Electrospinning is scalable and has been used to process a wide range of materials and composites with controllable mechanical properties through simple low-cost operation. Another emerging technique is 3D printing, which has the potential to serve as an essential fabrication process because of its ability to control bulk geometry and internal structure of tissue scaffolds.⁹ The advancement of bioprinting methods and compatible ink materials for bone and other musculoskeletal tissue engineering has been a major focus in the development of optimal 3D scaffolds. Three general strategies have been adopted for the creation of tissue constructs: to use isolated cells or cell substitutes; to use acellular biomaterials/scaffolds that are capable of inducing tissue regeneration in vivo; and to use a combination of cells and materials typically in the form of scaffolds.² This chapter reviews recent advancements in the development of scaffolds for orthopaedic tissue repair and regeneration through regenerative engineering.

Electrospinning and 3D printing of polymers and composites are two of the most important recent methods gaining widespread applications in orthopaedics. The term “electrospinning” derived from “electrostatic spinning,” first began to be used for tissue regeneration purposes in the late 1990s by Laurencin and his colleagues, with the first publication in the field in 2002.¹⁰ The principle of electrospinning involves the application of a high electric field to a droplet of a fluid coming from the tip of a die, which acts as one of the electrodes. This leads to deformation of the droplet and finally to the ejection of a charged jet from the tip of the cone, accelerating toward the counter electrode and leading to the formation of continuous fibers.^11,12 Some of the major parameters influencing the formation of bead-free continuous fibers include polymer properties, solvent properties, solution flow rate, applied voltage, distance from needle to collector, and rheological properties of solution, among others.^1,3

A wide variety of natural and synthetic polymers and their blends with composites and bioactive factors have been electrospun. Moreover, further modifications by posttreatment (ie, surface modification and thermal treatment) can be used to enhance the bioactivity of the electrospun scaffolds.² Multiaxial (coaxial/triaxial) structures with desired alignment (eg, uniaxially aligned, radially aligned, or wavy) can also be achieved through electrospinning.^13,14,15 The order of fibers or 3D architecture can be controlled by layer-by-layer stacking, 3D weaving, and template deposition.² These unique anisotropic structures and fibrous architectures of different musculoskeletal tissue can be recapitulated by scaffolds fabricated using electrospinning.² For example, biomimetic 3D scaffolds were created by orienting biocompatible polyphosphazene-polyester nanofiber matrices with fiber diameter of 50 to 500 nm in a concentric manner with an open central cavity to replicate bone
marrow cavity, as well as the lamellar structure of bone. In vitro culture with primary osteoblasts demonstrated that the biomimetic scaffolds promoted osteoblast proliferation and differentiation throughout the scaffold architecture, leading to a similar cell-matrix organization to that of native bone (Figure 2). The acellular biomaterials/scaffolds in electrospun materials may be divided into surface modified, blended, and composite scaffolds. Over the years, a combination of one or more types has been proved to be beneficial.