Regenerative Engineering in the Field of Orthopedic Surgery

Tissue Regeneration and the Role of Regenerative Engineering

Regeneration mimics the natural processes of tissue formation that occurs during several stages of an organism’s development. Tissues normally form during fetal phase of life termed embryonic tissue formation, tissue growth and development (fetal and postnatal), remodeling (degradation-formation), and healing (repair vs. regeneration). It is important to distinguish the difference in functionality that exists in repaired tissue that forms during the normal healing process, and that tissue would be created through regenerative engineering methods.

One aspect of regenerative engineering focuses on using cues from earlier tissue-formation periods and applies them to situations and injuries that occur later. This is performed in the hopes of directing adult tissue away from simple repair, where a defect in the tissue fills with relatively biologically inactive, nonfunctional tissues such as scar. Wound healing is a conserved evolutionary process among species and encompasses processes including inflammation, blood clotting, and cellular proliferation and extracellular matrix (ECM) remodeling which leads to distinct scar formation. Regeneration on the other hand would result in tissues where the defect or injury fills with a regenerate that is indistinguishable from the original surrounding native tissues.

Tissue gaps or large scars present biological challenges that have significant clinical consequences. For example, infarcts secondary to pulmonary emboli or myocardial infarctions result in relatively noncompliant scars taking the place of biologically active tissues that reduce the overall function of the organ as the scar cannot carry out the roll of the organ. The inferior scar tissue fails to emulate the tissue’s original structure and composition. In addition to the scar replacing the native, functional tissue, the scar also impedes the function of the rest of the organ due to physical forces restricting the dynamic movement of the tissue. These gaps or scars can be focused in a single area as in the case of infarction but can also be diffusely distributed in the native, normal tissue as in the case of infection. Even focal injuries can result in congestive heart failure in the case of myocardial infarction and restrictive lunch disease in the case of pulmonary embolism. Disease processes can also result in more diffuse changes in the affected tissue. Classically in the case of hand cellulitis, the compliance of the soft tissues is reduced after the infection has cleared, resulting in joint capsule contracture as well as generation restriction throughout the skin and muscle resulting in reduced range of motion, discomfort, and difficulty with fine motor movements. Similarly, diffuse changes that affect the compliance of tissues can be seen in certain autoimmune disorders such as systemic sclerosis, a chronic multisystem autoimmune disease characterized by a vasculopathy, diffuse fibrosis of skin and various internal organs, and immune abnormalities.

Regenerative engineering seeks to create physical and biological solutions for biological deficiencies. Ideally, when materials are used, engineered matrices are involved so that they can create appropriate and appropriately timed biological and physical signals to pluripotent cells within the surrounding tissues to stimulate the formation of bioidentical tissues that are contiguous with the surrounding biological environment. The implants simultaneously act as templates and guides for tissue ingrowth and incorporation. The choice of materials used for these scaffolds, any biologics that are incorporated into their physical arrangement and structure, and the nature in which they are assembled can have dramatic impacts on the ability of the stem cells to differentiate into tissues and ultimately function in the context of the musculoskeletal system.

When a regenerative engineering problem is approached, the engineer must decide on what strategy they would like to use for multitissue structure regeneration. In nature, most tissue development occurs during embryonic development, remodeling of existing tissues, or injury healing. Each regeneration strategy may include completely differing signaling cues as to stimulate growth. For example, the engineer needs to recapitulate embryonic/developmental conditions with appropriate precursor cells and/or extracellular matrices or, if appropriate, instead provide conditions (cells and matrix) that favor tissue formation of regenerated tissue from surrounding adult tissue.

The most common approach is to establish the growth of tissues within scaffolds in vitro. This traditional approach is an important testing ground to establish proof of concept experiments that determine which developmental biochemical cues induce the desired tissue proliferation. The developmental signals used during in vitro tissue engineering and propagation can include signal transduction molecules, cofactors, and growth factors. The in vitro approach can be controlled but is limited and does not fully recapitulate the in vivo environment.

The in vivo environment may have many other, complex, structural, physical, or systemic cues that contribute to tissue development and function. For example, one must consider gradient signals associated with tissues, such as hypoxia to stimulate angiogenesis, interactions with the endocrine system or hormones, or physical load to stimulate bone growth and remodeling. However, there are other challenges associated with the in vivo environment which make experiments in live animals challenging to control and interpret.

To take advantage of the in vivo setting and thus the biological environment surrounding the injured area and mechanical stimuli, the regenerative engineer will lose some of the overall control of the experimental settings. An in vivo approach, in combination with implants that use advanced technology in materials engineering, signal transduction, and surgical techniques to facilitate the growth of complex tissues and structures, increases the scope of medical problems that can be addressed and also minimizes the duration of time tissue regeneration takes by simultaneously growing multiple types of tissue rather than needing sequential reconstructive procedures. Through the formation of implants using advanced biomaterials and techniques, the regenerative engineer is setting the stage for tissue growth and development to happen in vivo rather than solely in a petri dish.