Bone morphogenetic protein-2 (BMP-2) is currently the only FDA approved osteoinductive growth factor used as a bone graft substitute. However, with increasing clinical use of BMP-2, a growing and well-documented side effect profile has emerged. This includes postoperative inflammation and associated adverse effects, ectopic bone formation, osteoclast mediated bone resorption, as well as inappropriate adipogenesis. Several large-scale studies have confirmed the relative frequency of adverse events associated with the clinical use of BMP-2, including life-threatening cervical spine swelling. In fact, the Food and Drug Administration (FDA) has issued a warning of the potential life threatening complications of BMP-2. This review will summarize the known adverse effects of BMP-2, including controversial areas such as tumorigenesis. Next, select animal models that replicate BMP-2’s adverse clinical effects will be discussed. Finally, potential molecules to mitigate the adverse effects of BMP-2 are reviewed. In summary, BMP-2 is a potent osteoinductive cytokine that has indeed revolutionized the bone graft substitute market; however, it simultaneously has accrued a worrisome side effect profile. Better understanding of these adverse effects among both translational scientists and clinicians will help determine the most appropriate and safe use of BMP-2 in the clinical setting.

In the last half-century, the development of biodegradable polymeric materials for biomedical applications has advanced significantly. Biodegradable polymeric materials are favored in the development of therapeutic devices, including temporary implants and three-dimensional scaffolds for tissue engineering. Further advancements have occurred in the utilization of biodegradable polymeric materials for pharmacological applications such as delivery vehicles for controlled/sustained drug release. These applications require particular physicochemical, biological, and degradation properties of the materials to deliver effective therapy. As a result, a wide range of natural or synthetic polymers able to undergo hydrolytic or enzymatic degradation is being studied for biomedical applications. This review outlines the current development of biodegradable natural and synthetic polymeric materials for various biomedical applications, including tissue engineering, temporary implants, wound healing, and drug delivery.

The major Food and Drug Association–approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL.

Adipose tissue is an ideal source of mesenchymal stem cells for bone tissue engineering: it is largely dispensable and readily accessible with minimal morbidity. However, the stromal vascular fraction (SVF) of adipose tissue is a heterogeneous cell population, which leads to unreliable bone formation. In the present study, we prospectively purified human perivascular stem cells (PSCs) from adipose tissue and compared their bone-forming capacity with that of traditionally derived SVF. PSCs are a population (sorted by fluorescence-activated cell sorting) of pericytes (CD146+CD34−CD45−) and adventitial cells (CD146−CD34+CD45−), each of which we have previously reported to have properties of mesenchymal stem cells. Here, we found that PSCs underwent osteogenic differentiation in vitro and formed bone after intramuscular implantation without the need for predifferentiation. We next sought to optimize PSCs for in vivo bone formation, adopting a demineralized bone matrix for osteoinduction and tricalcium phosphate particle formulation for protein release. Patient-matched, purified PSCs formed significantly more bone in comparison with traditionally derived SVF by all parameters. Recombinant bone morphogenetic protein 2 increased in vivo bone formation but with a massive adipogenic response. In contrast, recombinant Nel-like molecule 1 (NELL-1; a novel osteoinductive growth factor) selectively enhanced bone formation. These studies suggest that adipose-derived human PSCs are a new cell source for future efforts in skeletal regenerative medicine. Moreover, PSCs are a stem cell-based therapeutic that is readily approvable by the U.S. Food and Drug Administration, with potentially increased safety, purity, identity, potency, and efficacy. Finally, NELL-1 is a candidate growth factor able to induce human PSC osteogenesis.

Wound extracellular matrix is a key regulator of cell adhesion, migration, proliferation, and differentiation during cutaneous repair. The amount and organization of normal wound extracellular matrix are determined by a dynamic balance among overall matrix synthesis, deposition, and degradation. Matrix metalloproteinases (MMPs) are one family of structurally related enzymes that have the collective ability to degrade nearly all extracellular matrix components. The MMPs are broadly categorized into collagenases, gelatinases, stromelysins, and membrane-type MMPs by their substrate specificity. The aim of this study was to characterize the temporal changes in mRNA profiles for rat collagenase [matrix metalloproteinase-1 (MMP-1)], gelatinase A (MMP-2), matrilysin (MMP-7), gelatinase B (MMP-9), and membrane type 1-MMP (MT1-MMP), as well as tissue inhibitor of metalloproteinases-1 (TIMP-1), TIMP-2, and TIMP-3 during the inflammatory, granulation, and early remodeling phases of excisional skin repair. Eight full-thickness skin wounds were made on the backs of each rat (7-mm2 wounds; 16 rats;n = 128 wounds). Two animals at a time were reanesthetized, and all eight wounds on each animal were excised at 12 and 24 hours and at 2, 3, 5, 7, 10, and 14 days after injury. Six wounds from each animal were excised for RNA isolation, whereas two wounds were excised for histology. Controls consisted of nonwounded skin from identical locations in four animals. Total RNA from each time point was isolated and relative mRNA quantitation performed by using reduced-cycle reverse transcription-polymerase chain reaction. Correct polymerase chain reaction product amplification was confirmed by probing the blotted polymerase chain reaction product with a 32P-labeled oligonucleotide specific for a given MMP or TIMP. We demonstrated that the majority of MMP and TIMP mRNA induction and peak expression coincided temporally with the well-characterized inflammatory and granulation stages of repair. In conclusion, there is a distinct pattern of MMP and TIMP expression during normal excisional wound repair.

Both acute and chronic tendinopathy result in high morbidity, requiring management that is often lengthy and expensive. However, limited and conflicting scientific evidence surrounding current management options has presented a challenge when trying to identify the best treatment for tendinopathy. As a result of shortcomings of current treatments, response to available therapies is often poor, resulting in frustration in both patients and physicians. Due to a lack of understanding of basic tendon-cell biology, further scientific investigation is needed in the field for the development of biological solutions. Optimization of new delivery systems and therapies that spatially and temporally mimic normal tendon physiology hold promise for clinical application. This review focuses on the clinical importance of tendinopathy, the structure of healthy tendons, tendon injury, and healing, and a discussion of current approaches for treatment that highlight the need for the development of new nonsurgical interventions.