Clinicians and scientists working in the field of regenerative engineering are actively investigating a wide range of methods to promote musculoskeletal tissue regeneration. Small molecule-mediated tissue regeneration is emerging as a promising strategy for regenerating various musculoskeletal tissues and a large number of small molecule compounds have been recently discovered as potential bioactive molecules for musculoskeletal tissue repair and regeneration. In this review, we summarize the recent literature encompassing the past four years in the area of small bioactive molecule for promoting repair and regeneration of various musculoskeletal tissues including bone, muscle, cartilage, tendon, and nerve.

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Musculoskeletal regenerative engineering approach using small bioactive molecules in conjunction with advanced materials has emerged as a highly promising strategy for musculoskeletal repair and regeneration. Advanced biomaterials technologies have revealed nanofiber-based scaffolds for musculoskeletal tissue engineering as vehicles for the controlled delivery of small molecule drugs. This review article highlights recent advances in nanofiber-based delivery of small molecules for musculoskeletal regenerative engineering. The article concludes with perspectives on the challenges and future directions.

The demand for bone grafts has led to advances in regenerative engineering, a field at the intersection of advanced biomaterials, stem cell science, physics, developmental biology, and clinical translation. In this work, the authors evaluated a hybrid nanofiber/microsphere matrices both in vitro and in vivo for its ability to promote bone regeneration. Quantitative measures of cellular characteristics in vitro showed a higher fraction of marrow stromal cells with collagen promoter activity on hybrid matrices compared to control matrices (41% vs. 24%, p = 0.02). Control and hybrid matrices were then implanted for 6 weeks in calvarial defects of mice, and the animals received a single injection of calcein 1 day prior to sacrifice to visualize bone formation. Cryohistology of the undecalfied implants were evaluated for markers of bone mineralization, which revealed evidence of higher levels of bone tissue formation in hybrid matrices compared to controls. These data provide support that nanofiber-permeated, sintered, composite microsphere matrices may be a particularly useful matrix for the regenerative engineering of bone.

Bone is an essential organ for health and quality of life. Due to current shortfalls in therapy for bone tissue engineering, scientists have sought the application of synthetic materials as bone graft substitutes. As a composite organic/inorganic material with significant extra cellular matrix (ECM), one way to improve bone graft substitutes may be to engineer a synthetic matrix that is influenced by the physical appearance of natural ECM networks. In this work, the authors evaluate composite, hybrid scaffolds for bone tissue engineering based on composite ceramic/polymer microsphere scaffolds with synthetic ECM-mimetic networks in their pore spaces. Using thermally induced phase separation, nanoscale fibers were deposited in the pore spaces of structurally sound microsphere-based scaffold with a density proportionate to the initial polymer concentration. Porosimetry and mechanical testing indicated no significant changes in overall pore characteristics or mechanical integrity as a result of the fiber deposition process. These scaffolds displayed adequate mechanical integrity on the scale of human trabecular bone and supported the adhesion and proliferation of cultured mouse calvarial osteoblasts. Drawing from natural cues, these scaffolds may represent a new avenue forward for advanced bone tissue engineering scaffolds.

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The current gold-standard therapeutic strategies for bone grafts in the patient population are to use either allograft or autograft bone. Although these approaches have a long track record of utilization, neither is without risk to the patient, and there remains a desire in the field to improve treatment options. While there have been treatments approved by the FDA for full length growth factors and calcium salt-laden collagen sponges, these are not available for the entire population of potential bone graft patients. One viable strategy to focus on these concerns is to design an implantable bone graft substitute that can address all the negative drawbacks of autograft bone, allograft bone, and full length proteins. The work provides a preliminary investigation of synthetic, nanofiber-permeated, composite polymer/ceramic scaffold for bone repair using thermally induced phase separation, PLLA microspheres, and hydroxyapatite. The scaffolds as described have fiber diameters that mimic natural collagen ECM networks in bone as determined by scanning electron microscopy and will serve as the basis for future studies in substrate-guided bone tissue regeneration.