2.79J/3.96J/20.441/HST522J REGENERATION OF JOINT TISSUES Bone Massachusetts Institute of Technology Harvard Medical School Brigham and Women’s Hospital VA Boston Healthcare System M. Spector, Ph.D.CONFLICT OF INTEREST STATEMENT Prof Spector derives royalty income from certain products referred to as Bio-Oss, from Geistlich Pharma (Wolhusen, Switzerland).TISSUES COMPRISING JOINTS Permanent Regeneration Prosthesis Scaffold Bone Yes Yes Articular cartilage No Yes* Meniscus No Yes* Ligaments No Yes* Synovium No No * In the process of being developedTYPES OF TISSUES Which Tissues Can Regenerate Spontaneously? Yes No Connective Tissues • Bone √ • Articular Cartilage, Ligament, Intervertebral Disc, Others √ Epithelia (e.g., epidermis) √ Muscle • Cardiac, Skeletal √ • Smooth √ Nerve √FACTORS THAT CAN PREVENT REGENERATION • Size of defect – e.g., bone does not regenerate in large defects – Solution: fill defect with osteoconductive particles that adapt to the cavity or a form-filling absorbable “cement” • Collapse of surrounding tissue into the defect – e.g., periodontal defects – Solution: membranes for guided tissue regeneration (GTR) • Excessive strains in the reparative tissue – e.g., unstable fractures – Solution: fracture fixation apparatus • DiseaseELEMENTS OF TISSUE ENGINEERING/ REGENERATIVE MEDICINE • SCAFFOLD – Porous, absorbable synthetic (e.g., polyglycolic acid) and natural (e.g., collagen) biomaterials • CELLS (Autologous or Allogeneic) – Differentiated cells of same type as tissue – Stem cells (e.g., bone marrow-derived) – Other cell types (e.g., dermal cells) • REGULATORS – Growth factors or their genes – Mechanical loading – Static versus dynamic culture (“bioreactor”) * Used individually or in combination, but often with a scaffold)CASE STUDY Problem • 56-year-old man received ablative tumor surgery 8 years previously in the form of a subtotal mandibulectomy. • 7 cm had been bridged with a titanium reconstruction plate since initial surgery. • Head and neck region had been further compromised by radiation treatment. • Because he had been given Warfarin for an aortic valve replacement bony defects had to be kept to a minimum to avoid major postoperative bleeding. PH Warmke, et al., Lancet 364:766 (2004)Image of patient’s skull and mandible implant removed due to copyright restrictions. How to regenerate the mandible? • Wound healing compromised by radiation treatment • Limited blood supply to the area due to radiation treatment • Inability to harvest bone for grafting, due to Warfarin treatmentImage of patient’s skull and mandible implant removed due to copyright restrictions. Scaffold ? Cells ? Regulators ? How to regenerate the mandible? • Wound healing compromised by radiation treatment • Inability to harvest bone for grafting • Limited blood supply to the areaCASE STUDY Solution • Grow a subtotal replacement mandible inside the latissimus muscle with full bony continuity. • Provide an adequate vascular network to allow for subsequent transplantation of a viable graft into the defect. • Ensure that the replacement is shaped to the defect, thus improving the chances of adequate postoperative function and a satisfactory esthetic result. PH Warmke, et al., Lancet 364:766 (2004)CASE STUDY Methodology • 3D CT of the patient’s head to design a virtual replacement of the missing part of the mandible with computer-aided design. • A titanium mesh scaffold was then formed onto the model, which was subsequently removed. • The titanium mesh cage was filled with ten bone mineral blocks which were coated with 7 mg recombinant human BMP-7 embedded in 1 g bovine type 1 collagen. • 20 mL bone marrow was aspirated from the right iliac crest to provide undifferentiated precursor cells as a target for recombinant human BMP-7. • Bone marrow was mixed with 5 g natural bone mineral of bovine origin (particle size 0·5–1·0 mm) and this mixture was used to fill the gaps among the blocks inside the cage. • The titanium mesh cage was then implanted into a pouch of the patient’s right latissimus dorsi muscle.CASE STUDY Methodology • 7 weeks postop, transplantation of the mandibular replacement. • The replacement was harvested along with an adjoining part of the latissimus dorsi muscle containing the thoracodorsal artery and vein that had supplied blood for the entire transplant. • This pedicled bone-muscle flap was then transplanted into the defect site via an extraoral approach. • Minor bone overgrowth on the ends of the replacement was curetted to fit the transplant easily into the defect. • After the old titanium reconstruction plate was removed, the mandibular transplant was fixed onto the original mandible stumps with titanium screws, returning the contour of the patient’s jaw line to roughly that present before the mandibulectomy. • The vessel pedicle was then anastomosed onto the external carotid artery and cephalic vein by microsurgical techniques.Several slides containing images from the Lancet paper removed due to copyright restrictions.INCUBATION OF TISSUE ENGINEERING CONSTRUCTS IN ECTOPIC SITES • Allows for implantation of a mature, functional tissue engineered implant immediately upon excision of the lesion/tumor – Use of autologous cells • Allows for development of the construct in an in vivo (autologous) environment – Exposed to host cells and regulatory molecules – Not exposed to mechanical loading during development – Development can be monitored – At the appropriate stage of development the vascularized construct can be transplanted to the target defectSlide content removed due to copyright restrictions. Text and images describing INFUSE® Bone Graft, a recombinant human bone morphogenetic protein (rhBMP-2) in an absorbable collagen sponge. www.sofamordanek.comROLES OF THE BIOMATERIALS/ SCAFFOLDS (MATRICES) 1) the scaffold serves as a framework to support cell migration into the defect from surrounding tissues; especially important when a fibrin clot is absent. 2) serves as a delivery vehicle for exogenous cells, growth factors, and genes; large surface area. 3) before it is absorbed a scaffold can serve as a matrix for cell adhesion to facilitate/“regulate” certain unit cell processes (e.g., mitosis, synthesis, migration) of cells in vivo or for cells seeded in vitro. a) the biomaterial may