Biomaterials and Implants: Regenerative Engineering Approaches for Orthopaedics
Samuel J. Laurencin, MD, PhD
Wayne Cohen-Levy, MD, MS
Neither of the following authors nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter: Dr. Laurencin and Dr. Cohen-Levy.
ABSTRACT
Injury to musculoskeletal tissues often requires medical or surgical intervention to aid in recovery through repair or replacement. Natural and synthetic polymers without targeted tissue-specific biologic adjuncts to aid in repair are limited in their ability to fully restore native tissue biomechanical properties. Furthermore, readily available grafts for tissue repair or replacement are often lacking because of limited supply or donor-host geometric mismatch, among other challenges. The in vitro generation of native tissue that can then be used as replacements for compromised tissue has been explored as a means to overcome the limitations of contemporary treatment methods. Regenerative engineering has emerged as a field with broad applications, including the management of orthopaedic injuries. Through the deep convergence of materials science, stem cell technology, and developmental biology, it is anticipated that novel composite materials can be developed with scalable properties from the submicron level to bulk material macrostructure features. The production of a translational, patient-specific tissue, organ system, or limb would be the realization of the current potential of this field. It is important to explore current limitations of traditional materials and implant fabrication techniques, provide context for the general goals of regenerative engineering in replicating native tissues, and review the benefits and drawbacks of various scaffold preparation techniques including electrospinning and three-dimensional printing.
Keywords: biomaterials; electrospinning; regenerative engineering; three-dimensional printing
Introduction
Host and tissue-specific factors can affect the body’s self-repair capabilities, with adult articular cartilage being a prime example of a tissue with limited self-repair capabilities to any significant clinical and functional level. Management of musculoskeletal injuries often uses techniques focused on direct repair or replacement, which can be full or partial. Repaired tissues using traditional orthopaedic synthetic materials typically fail to regain their preinjury biomechanical functionality despite acceptable clinical outcomes that are often attainable. Polymers, ceramics, and metals are the primary classes of materials that have been used to support tissue healing1 (Table 1). When cells or cellular products are added to these materials, they act as scaffolds to support native tissue production and improved host tissue integration. Autografts and allografts have been cornerstones for tissue replacement when the outcome of direct repair would be unfavorable or not possible. Autografts are host-derived tissues and are ideal because of a lack of host immune response but are plagued by donor site morbidity. Allografts are tissues sourced externally from the intended recipient and circumvent the donor site morbidity of autografts. However, allografts place the patient at risk for immune system graft rejection and infection transmission, in addition to limitations on a readily available supply of size and geometry-matched graft options. Advances in scaffold fabrication techniques and the ability to direct in vitro and in vivo cellular behavior for targeted tissue repair or replacement have led to novel therapies that can overcome the current limitations of both autografts and allografts with great translational potential.
Table 1 Benefits and Limitations of Common Material Classes Used in Regenerative Engineering for Orthopaedic Applications | ||||||||||||||||||||||||
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Regenerative Engineering
The human body has tremendous self-repair capabilities through resident stem cells, but it can be severely limited in certain clinical settings or injury conditions. The physical distance between injured tissues in the setting of segmental long bone fractures compounded by the disruption of blood flow to the injury site is an example of a condition where self-repair potential is limited.2 Regenerative engineering exists as a deep convergence between materials science, stem cells, developmental biology, physical science, and clinical translation.3,4 This
field emerged in part through a need to address the limitations of contemporary approaches to management of musculoskeletal tissue injury, such as those evident with the use of autografts or allografts.5 Research in this field occurs from a top-down approach, gaining thorough understanding of the pathophysiology of clinical challenges and identifying points where engineering principles can be harnessed to halt and ultimately provide a new path for tissue regeneration and clinical functional improvement. Research can also occur in a bottom-up approach through a deep understanding of stem cells and cell signaling and how spatial and temporal factors through biomaterials and controlled exposure to growth factors, respectively, can yield the regeneration of native tissues.6 Ultimately, this field and the work being done within it aims to regenerate and not simply repair complex tissues and organ systems. For success and translation from the bench top to the bedside, a clear understanding of the clinical challenges for material integration and utilization must always be appreciated from the start. Gains are being made regularly with broad clinical applications, and the field of orthopaedics stands to gain much through continued investigation of regenerative engineering principles.
field emerged in part through a need to address the limitations of contemporary approaches to management of musculoskeletal tissue injury, such as those evident with the use of autografts or allografts.5 Research in this field occurs from a top-down approach, gaining thorough understanding of the pathophysiology of clinical challenges and identifying points where engineering principles can be harnessed to halt and ultimately provide a new path for tissue regeneration and clinical functional improvement. Research can also occur in a bottom-up approach through a deep understanding of stem cells and cell signaling and how spatial and temporal factors through biomaterials and controlled exposure to growth factors, respectively, can yield the regeneration of native tissues.6 Ultimately, this field and the work being done within it aims to regenerate and not simply repair complex tissues and organ systems. For success and translation from the bench top to the bedside, a clear understanding of the clinical challenges for material integration and utilization must always be appreciated from the start. Gains are being made regularly with broad clinical applications, and the field of orthopaedics stands to gain much through continued investigation of regenerative engineering principles.
Native tissues maintain a complex hierarchical structure, where the characteristics of the cell-tissue interaction on the nanoscale influence the microstructure tissue features, which in turn lead to the macrostructure material properties.7 Cellular vitality is supported through the transport of nutrients and oxygen and removal of waste through diffusion and integrated vascularity. Biomechanical integrity must be maintained for the tissues to provide functional support of organ systems. The cell-cell and cell-matrix interactions allow for maintenance of extracellular matrix using cell-specific signaling cascades and the influence of growth factors, matrix surface, and bulk features.6 Although great advances in biomaterials for orthopaedics have occurred, the ability for regenerative engineered structures to be incorporated into the human body while functioning in tandem with native tissues to generate a specific biomechanical group function remains difficult.8 To circumvent the limitations of single-tissue substitution, such as the potential for poor osteointegration in bone tissue engineering, the ability to replace complex tissue groups, joints, or complete limbs remains the overarching goal of regenerative engineering.9
Scaffold Design Considerations
The scaffold is the foundation for regenerative engineering applications as the replication of native extracellular matrix can aid in cellular differentiation and proliferation while also providing mechanical integrity for functional benefit.10 Collagen and proteoglycans, among other components in the extracellular matrix of musculoskeletal tissues, provide porosity and topography and the transport of growth factors to influence cellular behavior.11 High porosity allows for cell migration, nutrient transport, growth factor delivery, and waste removal.12,13 Of great importance in mesenchymal stem cell differentiation is the cell-matrix relationship, which can participate in cell-fate decisions.14 Because of the interrelationship with matrix components and water, mechanical integrity is inherent to the matrix, and mechanotransduction also has been found to influence cell function.15 More recently, the viscosity of the matrix, in particular, demonstrated importance in mechanotransduction through activation of YAP/TAZ mechanosensitive transcriptional activators, as discussed in a 2020 study.16 This highlights the complex and interactive nature of the native cellular environment and must be considered when developing biomaterials to direct cellular behavior in vitro and in vivo.
Regenerative engineering of bone is best supported by scaffolds displaying properties to promote osteoblast migration and proliferation (osteoconductive), progenitor cell differentiation (osteoinductive), and permitting well integration into the host local tissue environment (osteointegrative). Additional design criteria for regenerative engineering applications include (1) biocompatibility, (2) mechanical integrity based on the tissue’s native function, and (3) biodegradable products that do not cause local adverse tissue response and can be easily metabolized. The complex hierarchical nature of native bone requires a fabrication technique that can provide control on various scales of the scaffold, including submicron topography and macrostructure bulk material properties.17,18 A myriad of synthetic and natural biomaterials have been explored for regenerative medicine applications.19 Development of engineered tissues has been attempted via (1) cell-only substrates;20 (2) scaffold-only substrates with in vivo regeneration capability;21,22 or (3) a combination approach relying on the in vitro interaction between the cells and substrates.23 For example, ligament and tendon repair or regeneration has been explored using biodegradable polymers with and without inclusion of pluripotent stem cells with in vitro, in vivo, and some translational success.24 To permit cellular infiltration of scaffolds, various techniques have been explored to introduce porosity into the scaffolds. To date, scaffold manufacturing techniques such as freeze-drying, solvent casting with particle leaching, and gas foaming are
examples of fabrication techniques to create porous biocompatible scaffolds for orthopaedic applications.25,26 Figure 1 highlights common scaffold synthesis techniques used in regenerative engineering.27 Postsynthesis processing and functionalization or incorporation of growth factors can make scaffolds biomimetic and aid in in vitro and in vivo cellular response for improved scaffold functionality.6,28
examples of fabrication techniques to create porous biocompatible scaffolds for orthopaedic applications.25,26 Figure 1 highlights common scaffold synthesis techniques used in regenerative engineering.27 Postsynthesis processing and functionalization or incorporation of growth factors can make scaffolds biomimetic and aid in in vitro and in vivo cellular response for improved scaffold functionality.6,28
 Figure 1 Schematic illustration depicts common scaffold fabrication techniques. A, Solvent casting-particle leaching process. B, Gas foaming. C, Freeze-drying. D, Phase separation. E, Electrospinning. F, Rapid-prototyping. (Adapted with permission from Shi C, Yuan Z, Han F, Zhu C, Li B: Polymeric biomaterials for bone regeneration. Ann Joint 2016;1[9].) |
 Figure 2 A, Radiographs show comparison of polylactic acid (PLA) scaffolds with chitosan microspheres loaded with alendronate (CM-ALs [10%]) and those without alendronate (CM-ALs [0%]). The CM-AL (10%) scaffolds showed earlier and superior bone regeneration in the rabbit radius in vivo model. B, The scanning electron micrograph shows PLA scaffold (black arrow) and integrated microspheres (white arrow). (Adapted with permission from Wu H, Lei P, Liu G, et al: Reconstruction of large-scale defects with a novel hybrid scaffold made from poly (L-lactic acid)/nanohydroxyapatite/alendronate-loaded chitosan microsphere: in vitro and in vivo studies. Sci Rep 2017;7[1]:359.) |
A study explored large defect bone regeneration in a rabbit animal model using alendronate-loaded degradable chitosan microspheres in a polylactic acid-based scaffold, showing the benefit of a degradable scaffold phase for local delivery of agents to support native tissue regeneration29 (Figure 2). These more traditional scaffold fabrication techniques are often limited by challenges in rapid prototyping and scalability.30 Furthermore, the fabrication method of materials greatly influences the physical and mechanical properties attainable. Considering these facts, researchers have explored novel material fabrication techniques for regenerative engineering in orthopaedic applications.
Related posts:
Orthopaedic Patient Safety: Core Competencies and Communication Skills
New Technology in Orthopaedic Surgery: Robotics, Artificial Intelligence, and Machine Learning
Polytrauma Care
Rotator Cuff Disease, Calcific Tendinitis, Adhesive Capsulitis, Throwing Shoulder, and Instability
Ligament Injuries of the Wrist
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