Glatt, Vaida

ABSTRACT Regenerative rehabilitation is an emerging area of investigation that seeks to integrate regenerative medicine with rehabilitation medicine. It is based on the realization that combining these two areas of medicine at an early stage of treatment will produce a better clinical outcome than the traditional linear approach of first administering the elements of regeneration followed, after a delay, by rehabilitation. Indeed, in certain settings, a case can be made for initiating rehabilitation protocols before starting regenerative intervention. This review summarizes the contents of a workshop held during the 2018 annual meeting of the Orthopaedic Research Society. It introduced the concept of regenerative rehabilitation and then provided two orthopaedic examples drawn from the domains of cartilage repair and bone healing. Rehabilitation medicine can supply a variety of physical stimuli, including electrical stimulation, thermal stimulation and mechanical stimulation. Of these, mechanical stimulation has the most obvious relevance to orthopaedics. The mechano‐responsiveness of cartilage and bone has been known for a long time, but is poorly understood and has led to only limited clinical application. Improved bioreactor designs that allow multi‐axial loading enable new insights into the responsiveness of chondrocytes and chondroprogenitor cells to specific types of load, especially shear. Recent studies on the mechanobiology of bone healing show that modulating the mechanical environment of an experimental osseous lesion by a process of “Reverse Dynamization” soon after injury considerably enhances healing. Future studies are needed to probe the molecular mechanisms responsible for these phenomena and to translate these findings into clinical practice. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1263–1269, 2019.

Objectives: To develop and validate an unbiased, accurate, convenient, and inexpensive means of determining when an osseous defect has healed and recovered sufficient strength to allow weight bearing. Methods: A novel image processing software algorithm was created to analyze the radiographic images and produce a metric designed to reflect the bone strength. We used a rat femoral segmental defect model that provides a range of healing responses from complete union to nonunion. Femora were examined by x-ray, micro–computed tomography and mechanical testing. Accurate simulated radiographic images at different incident x-ray beam angles were produced from the micro–computed tomography data files. Results: The software-generated metric (SC) showed high levels of correlation with both the mechanical strength (τMech) and the polar moment of inertia (pMOI), with the mechanical testing data having the highest association. The optimization analysis yielded optimal oblique angles θB of 125 degrees for τMech and 50 degrees for pMOI. The Pearson R2 values for the optimized model were 0.71 and 0.64 for τMech and pMOI, respectively. Further validation using true radiographs also demonstrated that the metric was accurate and that the simulations were realistic. Conclusions: The preliminary findings suggest a very promising methodology to assess bone fracture healing using conventional radiography. With radiographs acquired at appropriate incident angles, it proved possible to accurately calculate the degree of healing and the mechanical strength of the bone. Further research is necessary to refine this approach and determine whether it translates to the human clinical setting.

Background: Reverse dynamization is a technology for enhancing the healing of osseous defects. With use of an external fixator, the axial stiffness across the defect is initially set low and subsequently increased. The purpose of the study described in this paper was to explore the efficacy of reverse dynamization under different conditions. Methods: Rat femoral defects were stabilized with external fixators that allowed the stiffness to be modulated on living animals. Recombinant human bone morphogenetic protein-2 (rhBMP-2) was implanted into the defects on a collagen sponge. Following a dose-response experiment, 5.5 μg of rhBMP-2 was placed into the defect under conditions of very low (25.4-N/mm), low (114-N/mm), medium (185-N/mm), or high (254-N/mm) stiffness. Reverse dynamization was evaluated with 2 different starting stiffnesses: low (114 N/mm) and very low (25.4 N/mm). In both cases, high stiffness (254 N/mm) was imposed after 2 weeks. Healing was assessed with radiographs, micro-computed tomography (μCT), histological analysis, and mechanical testing. Results: In the absence of dynamization, the medium-stiffness fixators provided the best healing. Reverse dynamization starting with very low stiffness was detrimental to healing. However, with low initial stiffness, reverse dynamization considerably improved healing with minimal residual cartilage, enhanced cortication, increased mechanical strength, and smaller callus. Histological analysis suggested that, in all cases, healing provoked by rhBMP-2 occurred by endochondral ossification. Conclusions: These data confirm the potential utility of reverse dynamization as a way of improving bone healing but indicate that the stiffness parameters need to be selected carefully. Clinical Relevance: Reverse dynamization may reduce the amount of rhBMP-2 needed to induce healing of recalcitrant osseous lesions, reduce the time to union, and decrease the need for prolonged external fixation.

ABSTRACTOrthopedic surgeons sometimes combine recombinant, human BMP‐2 with autograft bone when dealing with problematic osseous fractures. Although some case reports indicate success with this off‐label strategy, there have been no randomized controlled trials. Moreover, a literature search revealed only one pre‐clinical study and this was in a cranial defect model. The present project examined the consequences of combining BMP‐2 with particles of living bone in a rat femoral defect model. Human bone particles were recovered with a reamer‐irrigator‐aspirator (RIA). To allow acceptance of the xenograft as surrogate autograft, rats were administered an immunosuppressive cocktail that does not interfere with bone healing. Implantation of 200 µg living bone particles generated a small amount of new bone and defects did not heal. Graded amounts of BMP‐2 that alone provoked no healing (1.1 µg), borderline healing (5.5 µg), or full healing (11 µg) were added to this amount of bone particles. Addition of BMP‐2 (1.1 µg) increased osteogenesis, and produced bridging in 2 of 7 defects. The combination of BMP‐2 (5.5 µg) and bone particles made healing more reliable and advanced the maturation of the regenerate. Bone formation with BMP‐2 (11 µg) and bone particles showed improved maturation. Thus, the combination of autograft and BMP‐2 may be helpful clinically under conditions where the healing response is suboptimal. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2137–2145, 2016.Clinical significanceThese data support the clinical use of recombinant, human BMP‐2 with autograft bone when treating large segmental osseous defects. The combination leads to greater bone formation and accelerates the maturation of the regenerate.