Applications and Implications of Heparin and Protamine in Tissue Engineering and Regenerative Medicine

Table 2

Applications of F/P micro/nanoparticles (F/P M/NPs) as biomaterials for tissue engineering and regenerative medicine.

Biomaterial uses of F/P; micro/nanoparticles (F/P M/NPs)	Reported results	Year of publication	References
(1) Heparin neutralizer	(i) Protamine is a competent heparin neutralizer	1997	[37]
	(ii) Postimplantation administration of protamine reduced the thrombotic complication and remarkably reduced the lengthy bed rest period as well as the hospital stay of the patients
	(iii) Post-protamine injection reactions of the patients such as transient back pain, hypotension, and skin rashes were well managed in vitro
	(iv) Severe groin hematoma was observed at a minimal percentage
(2) Cell carriers	(i) F/P MPs enhanced the viabilities of various stem cells such as hMVECs, human dermal fibroblasts, and ADSCs in suspension culture	2010	[39]
	(ii) F/P MPs adhered into the surfaces of the cells, induced cell aggregation, and promoted cell growth
	(iii) Cell aggregates secreted increased amount of heparin-binding growth factors such as FGF
	(iv) F/P MPs induced neovascularization in nude mice model
	(v) Possible angiogenic biomaterial
	(i) When F/P MPs were coated on the culture plate, the quiescent state of hepatic stellate RI-T cells (HSCs) was conserved in comparison to those grown under noncoated and matrigel-coated plates	2012	[43]
	(ii) HSCs exhibited suppressed the expressions of collagen IαI and TGF-β 1 mRNA levels
	(i) F/P NPs reduced the expansion period of human multilineage ASCs and BMSCs despite the absence of animal serum	2012	[42]
	(ii) F/P NPs induced rapid proliferation rates of ASCs and BMSCs
	(iii) ASCs and BMSCs maintained their markers and exhibited their rapid multilineage differentiation
	(iv) F/P NP-coated plates are a useful substratum for the adherence and proliferation of ASCs and BMSCs despite low levels of PRP and FGF-2
	(i) F/P rapid cell proliferation rate of IR-ASCs under 3D-culture gel system at a low inbred-rat serum content	2013	[40]
	(ii) F/P expedited not only the local cell proliferation but also the vascularization and tissue granulation at the injection sites after transplantation
(3) Cytokine immobilizer or attractant/biomaterial for cell growth and differentiation	(i) Heparin MPs coating immobilized cytokines, namely, SCF, Tpo, and Flt-3 ligand	2009	[44]
	(ii) Controlled gradual release of the cytokines into the media was demonstrated to occur within 3-4 culture days
	(iii) Superior CD 34 (+) hematopoietic progenitor cells proliferation rates were shown at approximately 8.0-fold and over 31.9-fold after 6 and after 12 culture days, respectively
	(i) F/P controlled the gradual release of heparin-binding growth factors like FGF-2 and cytokines such as IL-3 and GM-CSF into the culture media	2009	[41]
	(ii) F/P enhanced the cell growth of hMVECs, human dermal fibroblast cells (hDFCs), and hematopoietic cell line (TF-1) cells when they were used coating agents despite the low level of FBS in the culture media
(4) Hair growth enhancer	(i) Dalteparin (F; identical to fragmin) and protamine microparticles injection (F/P MPs) facilitated increased hair growth	2011	[7]
	(ii) Microscopic findings showed thickened epithelium, proliferation of collagen fibers and fibroblasts, and increased vessels around follicles
	(iii) F/P MPs showed a promising therapeutic use in dermatology particularly on hair reconstruction for alopecia
(5) DNA/protamine injectable dental complex/drug carrier	(i) DNA/protamine complex delayed the growth of certain bacterial species, namely, Staphylococcusaureus, Pseudomonas aeruginosa, Porphyromonas gingivalis, and Prevotella intermedia	2011	[6]
	(ii) An effective drug carrier for gum pocket treatment
	(iii) DNA/protamine complex promoted GTR and GBR
(6) Protein carrier	(i) F/P MPs are competent carrier of the proteins present in the human PRP that stimulate neovascularization and granulation tissue formation	2011	[46]
	(ii) F/P MPs effectively adsorb growth factors GFs
	(iii) F/P MPs significantly enhanced neovascularization and filtration of inflammatory cells
	(i) F/P MPs are good carriers of proteins in PRP and optimized the growth of human aorta endothelial cells (AECs) as well as smooth muscle cells(SMCs)	2012	[45]
	(ii) Superior biological activities of GFs in PRP were demonstrated by the cultured AEC and SMCs treated with F/P MPs
	(iii) The increases in collateral arteries in ischemic limbs were significantly higher in the PRP-containing F/P MPs group than those in the F/P MPs alone, and PRP alone, in comparison to the control group.
(7) Injectable biomaterial to prevent skin flap necrosis	(i) Injection of PRP and F/P MPs prior to elevation of skin flaps enriched their survival and prohibited necrosis in rodent models	2011	[8]
	(ii) Histological analysis revealed that the skin flaps preinjected with PRP&F/P MPs exhibited thick granulation of tissues and neovascularization in comparison to the untreated groups
	(iii) PRP and F/P MPs are a promising injectable biomaterial in reconstructive surgery to prevent skin flap necrosis
(8) Growth factor (HGF,VEGF) carrier and inducer of neovascularization	(i) FGF-2 was bounded to F/P MPs and facilitated its protections against degradation, controlled release during the culture period	2009	[41]
	(ii) A week after injection, F/P MPs stimulated significant neovascularization and fibrous tissue formation
	(iii) F/P MPs biodegradation was observed 2 weeks after injection
	(i) No significant difference in blood pressure among the rabbit animal models of ischemia as revealed by laser Doppler perfusion imaging	2011	[4]
	(ii) A remarkable improvement of blood pressure was observable in animals treated with F/P MPs/FGF-2 compared to the untreated ones
	(iii) Cotreatment of F/P MPs and FGF 2 significantly induced collateral blood vessel formation in rabbit ischemic models
	(iv) F/P MPS/FGF 2-induced arteriogenesis and angiogenesis in ischemic limbs present a promising for peripheral artery disease (PAD)
	(i) HGF-containing F/P MPs substantially enhanced mitogenic effect of HGF on cultured human microvascular endothelial cells	2013	[5]
	(ii) The conjugation of HGF to F/P MPs facilitated the controlled release of HGF and protected these growth factors from heat and proteolytic inactivation
	(iii) F/P MPs are efficient HGF carriers that facilitate cell proliferation and vascularization of damaged tissues in mice models