Downloaded from http://journals.lww.com/annalsplasticsurgery by BhDMf5ePHKbH4TTImqenVChdHhRBUo+1INsdTb/S3BmQcIPOou3vC6kXHr4u99U6aHEe7q7Cpjc= on 05/27/2020 Injectable Microannealed Porous Scaffold for Articular Cartilage Regeneration Christine Schaeffer, MD, a Blaise N. Pfaff, BS, b Nicholas J. Cornell, BS, b Lisa S. Salopek, LVT, a Sarah Shan, BS, c Jan Viyar, BS, b Wilson Omesiete, MD, a Donald R. Griffin, PhD, b Patrick S. Cottler, PhD, a and Brent R. DeGeorge, Jr, MD, PhD a Background: The purpose of this study is to assess the feasibility of a novel mi- croporous annealed particle (MAP) scaffolding hydrogel to enable both articular cartilage and subchondral bone biointegration and chondrocyte regeneration in a rat knee osteochondral defect model. Methods: An injectable, microporous scaffold was engineered and modified to match the mechanical properties of articular cartilage. Two experimental groups were utilized—negative saline control and MAP gel treatment group. Saline and MAP gel were injected into osteochondral defects created in the knees of Sprague-Dawley rats. Photo-annealing of the MAP gel was performed. Qualita- tive histologic and immunohistochemical analysis was performed of the treated defects at 2, 4, and 8 weeks postsurgery. Results: The injectable MAP gel successfully annealed and was sustained within the osteochondral defect at each timepoint. Treatment with MAP gel resulted in maintained size of the osteochondral defect with evidence of tissue ingrowth and increased glycosaminoglycan production, whereas the control defects pre- sented with evidence of disorganized scar tissue. Additionally, there was no sig- nificant inflammatory response to the MAP gel noted on histology. Conclusions: We have demonstrated the successful delivery of an injectable, flowable MAP gel scaffold into a rat knee osteochondral defect with subsequent annealing and stable integration into the healing wound. The flowable nature of this scaffold allows for minimally invasive application, for example, via an arthro- scopic approach for management of wrist arthritis. The MAP gel was noted to fill the osteochondral defect and maintain the defect dimensions and provide a con- tinuous and smooth surface for cartilage regeneration, suggesting its ability to provide a stable scaffold for tissue ingrowth. Future chemical, mechanical, and bi- ological gel modifications may improve objective evidence of cartilage regeneration. Key Words: MAP gel, arthritis, osteochondral defects, cartilage regeneration (Ann Plast Surg 2020;84: S446–S450) A rthritis of the hand and wrist is a chronic, disabling condition that affects roughly 4 million Americans annually with an estimated annual cost in terms of health care expenditure and decreased produc- tivity exceeding US $300 billion. 1 Osteoarthritis (OA) is characterized by progressive, irreparable loss of articular cartilage due to its limited intrinsic repair capacity because of its relative lack of blood supply and low cellular proliferation rate. Therefore, current treatment strategies are focused on replenishing the lost articular cartilage. Osteochondral grafting and autologous chondrocyte implantation have been used to re- place degenerated or damaged cartilage. 2,3 These methods have shown limited long-term efficacy and do not significantly modify OA symp- toms. 4 Many hypothesize that these methods of chondrocyte transplanta- tion failed, in part, due to the lack of nourishing environment to promote chondrogenesis. 5 Additionally, transplantation of cartilage is an open, invasive procedure. A major obstacle in the management of OA remains the inability to effectively restore articular cartilage, restricting the options for pa- tients to continued nonoperative management, joint replacement, or ablation in the form of arthroplasty or arthrodesis. Tissue-engineered cartilage replacements represent an innovative approach to promote the development of functional articular cartilage and potentially avoid total joint replacement. However, the optimum mechanical and biochemical properties of the substrate material have yet to be defined, and leakage of the substrate, inadequate integration of host tissue, and insufficient structural support are common problems in tissue-engineered approaches. 6 To address these issues, we propose the implementation of a rel- atively new class of injectable biomaterial utilizing microgel building blocks to assemble a microporous annealed particle (MAP) scaffold in response to a light stimulus. Once stimulated by light, the injected microspheres are chemically annealed to one another (and surrounding tissue) through permanent covalent bonds to form a solid and hyperporous scaffold to support tissue ingrowth. 7 This porous biomate- rial allows for an accelerated window of tissue biomaterial integration, and the flowable nature makes the MAP gel an ideal candidate for ar- throscopic procedures, for example, in the treatment of wrist OA. Each microparticle is created using extremely tunable synthetic hydrogel chemistry and can be engineered to match the mechanical and chemical needs of the environment. For this study, we have chosen to adapt our previous formulations that have been used in skin 7 and brain lesions 8 to take advantage of the high level of tissue integration and lack of im- munogenicity. More specifically, we increased the microparticle stiffness and mechanism of degradation (ie, removal of protease-sensitive peptide linker) to produce a MAP scaffold specialized for long-term treatment of cartilage. We hypothesize that MAP gel implantation in a rat knee osteochondral defect model would provide a scaffold for tissue regener- ation and allow for both cartilage and subchondral bone biointegration. MATERIALS AND METHODS Animals Animal experiments were performed under a protocol approved by the University of Virginia Institutional Animal Care and Use Com- mittee (Animal Welfare Assurance A3245-01) in accordance with the National Institutes of Health's Guide for the Care and Use of Laboratory Animals. Six- to 8-week-old Sprague-Dawley rats (300–370 g) housed in an assessment and accreditation of laboratory animal care-accredited facility were utilized for the study. Received October 31, 2019, and accepted for publication, after revision December 2, 2019. From the a Department of Plastic Surgery, b Department of Biomedical Engineering, and c School of Medicine, The University of Virginia, Charlottesville, VA. Conflicts of interest and sources of funding: South Eastern Society of Plastic and Reconstructive Surgery Research Grant, 2018. University of Virginia, Center for Engineering in Medicine Seed Grant. The authors declare no conflict of interest. Financial Disclosure Statement: D.R.G. is the inventor of the microannealed porous scaffold. This article was presented in the resident section of the 62nd Annual Meeting of the Southeastern Society of Plastic and Reconstructive Surgeons on June 12, 2016, in Naples, FL. Reprints: Patrick S. Cottler, PhD, Department of Plastic Surgery, University of Virginia Health System, P.O. Box 800376, Charlottesville, VA 22908. E-mail: psc5d@hscmail.mcc.virginia.edu. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0148-7043/20/8405–S446 DOI: 10.1097/SAP.0000000000002271 RESEARCH ARTICLES S446 www.annalsplasticsurgery.com Annals of Plastic Surgery • Volume 84, Supplement 5, June 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.