Table 2.

Biomaterial modification strategies to address the challenges of CMF defect repair

Challenge	Ideal properties	Methods to address	Ref.
Mechanics
Surgical handling	Easy for surgeons to add to defect	3D-printing exact defect shape Shapeable by surgeon (i.e. putty) Trimmable material (i.e. sheet)	61, 90, 93–95
Stiffness	Should not be stiffer than bone to avoid stress-shielding and not too soft to avoid material collapse	Avoid stiff metal materials Create composite structures to increase stiffness of soft materials Cross-linking to add stiffness	78 and 91
Micromotion	Limit to 28–150 μm of motion or else fibrosis will occur	Design implant with shape-fitting properties	61, 79 and 93
Bacterial infection
Infection	Killing bacteria or preventing bacterial adhesion to implant surface without antibiotics	Nano-scale surface topography kills bacteria (i.e. pillars or unique patterns) Compositional changes can kill bacteria or prevent attachment: Antimicrobial peptides and enzymes Hydrophobic coatings Metal nanoparticles Natural materials (i.e. honey, chitosan)	101–104, 113 and 115
Immune response
Macrophage phenotype	M1 to M2 transition over weeks	Porous material facilitates healing, >30 μm pore size to promote M2 Patterned surfaces or anisotropic pores promote macrophage elongation and M2 phenotype	121 and 123
Foreign body response (FBR)	Avoid material causing FBR	Degradation byproducts should not be cytotoxic or in high quantities Particles sizes <2 μm can cause FBR and bone resorption Avoid thick, hard to degrade materials Avoid designing materials with points or sharp edges	124–128
Balancing multiple cell types
Mesenchymal stem cells, osteoblasts, and osteocytes	Osteogenesis and differentiation to the bone lineage	Metal particles such as zinc and magnesium can induce osteogenesis Pore sizes > 50 μm can induce osteogenesis Aligned fibers and pores promote bone formation over random orientations Increasing stiffness increases osteogenesis Mineral (Ca, P) promotes MSC differentiation and osteogenesis Glycosaminoglycans (i.e. Chondroitin-6-sulfate, heparin sulfate) induce osteogenesis	75, 134, 138, 145 and 150
Osteoclasts	Limit early resorptive activity of implant	Calcium enhances OPG production to block osteoclastogenesis	133 and 136
Pericytes and endothelial cells	Promote angiogenesis and fully formed and functional vasculature	Stiffer materials encourage angiogenesis and endothelial cell spreading Aligned or channel-like pores can guide vessel formation Larger pores are better at promoting angiogenesis	146, 148 and 149
Regenerative healing
Host bone regeneration	New bone should form throughout the material without voids	Micro-scale porosity enhances bone formation throughout implants Metals do not allow for new bone formation	157 and 158
Material degradation	Material degradation should match host bone regeneration	Thinner materials allow for quicker degradation Ideally a material should degrade within 3–6 months for CMF defect repair Polymer chemistry can be modified to hasten degradation by pH changes, temperature, and hydrolysis Mechanical stimuli can help to balance degradation and regeneration	6,155 and 156